Publications by authors named "Weiling He"

48 Publications

Influence of Contrast Agent Injection Scheme Customized by Dual-Source CT Based on Automatic Tube Voltage Technology on Image Quality and Radiation Dose of Coronary Artery Imaging.

Front Surg 2022 5;9:862697. Epub 2022 Apr 5.

Diagnostic Radiology Department, Hunan Cancer Hospital, Changsha, China.

Objective: To explore the influence of a contrast agent injection scheme customized by dual-source CT based on automatic tube voltage technology on coronary imaging image quality and radiation dose.

Methods: A total of 205 patients who underwent coronary CT angiography (CCTA) in our hospital from June 2021 to September 2021 were selected. 105 patients in the control group who underwent routine scanning according to body mass (BMI) and 100 patients in the observation group who set tube voltage and contrast agent dosage according to automatic tube voltage selection technology. CT values of the aortic root (AO); left anterior descending (LAD) branch; proximal, middle, and distal segments of the right coronary artery (RCA); and proximal and distal segments of left circumflex (LCX) branch were measured. We calculated the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the image. Image quality scoring and effective dose (ED) calculation were carried out.

Results: There was no significant difference in the CT value, SNR value, and CNR value of each part of the artery between the two groups ( > 0.05). Image quality scores of the control group and the observation group were 1.28 ± 0.25 and 1.25 ± 0.23, respectively, and there was no significant difference in scores ( > 0.05). In the control group, the dosage of comparator was 43.81 ± 6.74 ml, and the ED was 4.92 ± 1.26 mSv. The dosage of contrast agent in the observation group was 34.23 ± 6.39 ml, and ED was 3.05 ± 0.94 mSv. The dosage of contrast agent and ED in the observation group were lower than those in the control group ( < 0.05).

Conclusion: The contrast agent injection scheme customized by dual-source CT based on automatic tube voltage technology can meet the clinical requirements of coronary image quality, reduce the radiation dose and contrast agent consumption, and help doctors choose a more accurate and reasonable examination scheme, which has certain clinical application value.
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http://dx.doi.org/10.3389/fsurg.2022.862697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018106PMC
April 2022

RNA mA methylation regulates dissemination of cancer cells by modulating expression and membrane localization of β-catenin.

Mol Ther 2022 Apr 14;30(4):1578-1596. Epub 2022 Jan 14.

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China. Electronic address:

N6-methyladenosine (mA) methylation, which is modified by the METTL3/METTL14 complex, is a dominant internal modification in mammalian RNA and tightly linked to cancer progression. Here we reveal that METTL3-promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) are associated with expression and membrane localization of β-catenin (encoded by CTNNB1), as opposed to Wnt signaling activation in various types of cancer cells, including cervical, lung, and liver cancer. Specifically, METTL3 regulates the transcription, mRNA decay, translation, and subcellular localization of β-catenin. For CTNNB1 expression, METTL3 indirectly suppresses CTNNB1 transcription by stabilizing its transcription suppressor E2F1 mRNA; deposition of 5'UTR mA in CTNNB1 promotes its decay in a content-dependent manner via YTHDF2 recognition; 5'UTR mA in CTNNB1 suppresses its translation efficiency, whereas the global METTL3 level controls the canonical and non-canonical translation of CTNNB1, which is probably associated with the interaction between YTHDF1 and eIF4E1/eIF4E3. For β-catenin translocation, METTL3 represses membrane localization of β-catenin and its interaction with E-cadherin by downregulating c-Met kinase, leading to inhibition of cell motility. In vitro, in vivo, and clinical analyses confirm the essential role of β-catenin and its expression regulators in cancer cell dissemination. The findings not only expand our understanding of mA modification and its roles in gene expression and subcellular localization of targets but also suggest that the METTL3/β-catenin axis might be a potential target to inhibit cancer metastasis.
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http://dx.doi.org/10.1016/j.ymthe.2022.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9077323PMC
April 2022

Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia.

Hepatology 2021 09;74(3):1461-1479

National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Background And Aims: Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC.

Approach And Results: From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC.

Conclusions: Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.
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http://dx.doi.org/10.1002/hep.31846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518375PMC
September 2021

-Methyladenosine Regulates mRNA Stability and Translation Efficiency of KRT7 to Promote Breast Cancer Lung Metastasis.

Cancer Res 2021 06 1;81(11):2847-2860. Epub 2021 Apr 1.

Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.

The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer lung metastasis cells by three rounds of selection of lung metastatic subpopulations and designated them as BC cells. In these cells, mRNA -methyladenosine (mA) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for mA-induced breast cancer lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, mA promotes breast cancer lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7. SIGNIFICANCE: This study suggests that -methyladenosine is a key driver and potential therapeutic target in breast cancer metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3779DOI Listing
June 2021

Methyladenosine Modification in RNAs: Classification and Roles in Gastrointestinal Cancers.

Front Oncol 2020 1;10:586789. Epub 2021 Feb 1.

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.

Cellular ribonucleic acids (RNAs), including messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), harbor more than 150 forms of chemical modifications, among which methylation modifications are dynamically regulated and play significant roles in RNA metabolism. Recently, dysregulation of RNA methylation modifications is found to be linked to various physiological bioprocesses and many human diseases. Gastric cancer (GC) and colorectal cancer (CRC) are two main gastrointestinal-related cancers (GIC) and the most leading causes of cancer-related death worldwide. In-depth understanding of molecular mechanisms on GIC can provide important insights in developing novel treatment strategies for GICs. In this review, we focus on the multitude of epigenetic changes of RNA methlyadenosine modifications in gene expression, and their roles in GIC tumorigenesis, progression, and drug resistance, and aim to provide the potential therapeutic regimens for GICs.
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http://dx.doi.org/10.3389/fonc.2020.586789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883673PMC
February 2021

Association of Preoperative Serum Carcinoembryonic Antigen and Gastric Cancer Recurrence: A Large Cohort Study.

J Cancer 2021 1;12(2):397-403. Epub 2021 Jan 1.

Center of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China.

Measuring postoperative carcinoembryonic antigen (CEA) is recommended by guidelines to help detecting recurrence of gastric cancer patients. However, the prognostic significance of elevated preoperative CEA is unclear. This study aims to investigate whether patients with elevated preoperative CEA have a higher risk of recurrence than patients with normal preoperative CEA. We conducted a retrospective cohort study at a gastric cancer center in South China. Consecutive patients with stage I to III gastric adenocarcinoma who underwent curative resection at the center from January 2001 to February 2016 were identified. Patients were grouped into two cohorts: normal preoperative CEA (≤ 5 ng/ml), and elevated preoperative CEA (> 5 ng/ml). 3-year recurrence-free survival (RFS) and hazard function curves over time were estimated. A total of 1,596 patients (1,063 {66.6%} male; median {Interquartile range, IQR} age, 59 {50-66} years) were identified. Patients with elevated preoperative CEA had 15.5% lower 3-year RFS (n=222 {70.4%}) than the cohorts with normal preoperative CEA (n=1,374 {85.9%}). The hazard function of recurrence for the two cohorts peaked at the similar time (around 10 months after surgery). Multivariate Cox analyses confirmed that elevated preoperative CEA was independently associated with shorter RFS (Hazard Ratio {HR}, 1.69; 95% confidence interval {CI}, 1.26-2.27; = 0.001). Patients with elevated preoperative CEA are at increased risk for recurrence, especially within the first 24 months after surgery.
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http://dx.doi.org/10.7150/jca.47899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738990PMC
January 2021

RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer.

Gut 2021 09 20;70(9):1698-1712. Epub 2020 Nov 20.

National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China

Objective: Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood.

Design: We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models.

Results: We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the mA methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models.

Conclusions: Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.
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http://dx.doi.org/10.1136/gutjnl-2020-320652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355885PMC
September 2021

A versatile UCST-type composite microsphere for image-guided chemoembolization and photothermal therapy against liver cancer.

Nanoscale 2020 Oct 30;12(38):20002-20015. Epub 2020 Sep 30.

School of Biomedical Engineering, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.

The development of novel chemoembolization agents to improve the treatment efficacy of transarterial chemoembolization (TACE) against liver cancer remains an urgent need in clinical practice. Herein, a versatile composite microsphere with upper critical solution temperature (UCST) properties was prepared to encapsulate polydopamine coated superparamagnetic iron oxide nanoparticles ([email protected]) and doxorubicin for simultaneous chemoembolization and photothermal therapy. The microspheres were spherical with an average diameter of 100-300 μm and exhibited favorable drug loading capability as well as strong photothermal effect. Strikingly, synergistic enhancement of photothermal therapy and chemotherapy against chemoresistant liver cancer cells was achieved. The in vivo therapeutic efficacy and safety evaluations were performed using rabbit VX2 liver tumor models. It was revealed that a single treatment of the combination of TACE and photothermal procedure resulted in 87.5% complete response and 12.5% partial response for the microsphere group, whereas all tumors in the control group progressed rapidly. Contrast-enhanced computed tomography (CT) evaluation indicated that the tumor diameter decreased by 91.5% after treatment, while that in the control group increased by 86.5%. The pathology-proven tumor necrotic rate was 87.2%, which significantly surpassed that of 65.2% in the control group. Furthermore, serum liver enzyme and biochemical studies indicated a temporary liver injury which can be fully recovered. Our findings demonstrated that this microsphere may be advantageous for enhancing therapeutic efficacy of TACE against liver cancer.
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http://dx.doi.org/10.1039/d0nr04592fDOI Listing
October 2020

RNA m A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.

EMBO J 2020 06 5;39(12):e103181. Epub 2020 May 5.

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

N6-methyladenosine (m A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m A modification in the resistance of HCC to sorafenib therapy.
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http://dx.doi.org/10.15252/embj.2019103181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298296PMC
June 2020

-methyladenosine-induced ERRγ triggers chemoresistance of cancer cells through upregulation of ABCB1 and metabolic reprogramming.

Theranostics 2020 10;10(8):3382-3396. Epub 2020 Feb 10.

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.

: Drug resistance severely reduces treatment efficiency of chemotherapy and leads to poor prognosis. However, regulatory factors of chemoresistant cancer cells are largely unknown. : The expression of estrogen receptor related receptors (ERRs) in chemoresistant cancer cells are checked. The roles of ERRγ in chemoresistance are confirmed by and studies. The mechanisms responsible for ERRγ-regulated expression of and are investigated. : The expression of ERRγ is upregulated in chemoresistant cancer cells. Targeted inhibition of ERRγ restores the chemosensitivity. ERRγ can directly bind to the promoter of to increase its transcription. An elevated interaction between ERRγ and p65 in chemoresistant cells further strengthens transcription of . Further, ERRγ can increase the fatty acid oxidation (FAO) in chemoresistant cells via regulation of the rate-limiting enzyme of FAO. The upregulated ERRγ in chemoresistant cancer cells might be due to increased levels of N6-methyladenosine (mA) can trigger the splicing of precursor mRNA. : mA induced ERRγ confers chemoresistance of cancer cells through upregulation of and
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http://dx.doi.org/10.7150/thno.40144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069076PMC
April 2021

Fatty Acid Oxidation Controls CD8 Tissue-Resident Memory T-cell Survival in Gastric Adenocarcinoma.

Cancer Immunol Res 2020 04 19;8(4):479-492. Epub 2020 Feb 19.

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.

The success of checkpoint inhibitors in cancer treatment is associated with the infiltration of tissue-resident memory T (Trm) cells. In this study, we found that about 30% of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment of gastric adenocarcinoma were CD69CD103 Trm cells. Trm cells were low in patients with metastasis, and the presence of Trm cells was associated with better prognosis in patients with gastric adenocarcinoma. Trm cells expressed high PD-1, TIGIT, and CD39 and represented tumor-reactive TILs. Instead of utilizing glucose, Trm cells relied on fatty acid oxidation for cell survival. Deprivation of fatty acid resulted in Trm cell death. In a tumor cell-T-cell coculture system, gastric adenocarcinoma cells outcompeted Trm cells for lipid uptake and induced Trm cell death. Targeting PD-L1 decreased fatty acid binding protein (Fabp) 4 and Fabp5 expression in tumor cells of gastric adenocarcinoma. In contrast, the blockade of PD-L1 increased Fabp4/5 expression in Trm cells, promoting lipid uptake by Trm cells and resulting in better survival of Trm cells and . PD-L1 blockade unleashed Trm cells specifically in the patient-derived xenograft (PDX) mice. PDX mice that did not respond to PD-L1 blockade had less Trm cells than responders. Together, these data demonstrated that Trm cells represent a subset of TILs in the antitumor immune response and that metabolic reprogramming could be a promising way to prolong the longevity of Trm cells and enhance antitumor immunity in gastric adenocarcinoma.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0702DOI Listing
April 2020

Complement C3 overexpression activates JAK2/STAT3 pathway and correlates with gastric cancer progression.

J Exp Clin Cancer Res 2020 Jan 13;39(1). Epub 2020 Jan 13.

Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

Background: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC.

Methods: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments.

Results: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor.

Conclusions: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression.

Trial Registration: ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.
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http://dx.doi.org/10.1186/s13046-019-1514-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956509PMC
January 2020

Global liver disease burdens and research trends: Analysis from a Chinese perspective.

J Hepatol 2019 07 12;71(1):212-221. Epub 2019 Mar 12.

Department of Health Sciences, National Natural Science Foundation of China, Beijing, China. Electronic address:

Liver diseases affect millions of people worldwide. In most developed countries, the incidence of viral hepatitis is waning as a result of modern advances in disease prevention, diagnosis, and therapies. Expanded programmes for systematic immunisation against hepatitis B virus have also significantly brought down the number of new cases in many countries, including China. In contrast, with the improvement in living standards, the prevalence of metabolic liver diseases including non-alcoholic fatty liver disease and alcohol-related liver disease is set to rise, ultimately leading to more cases of end-stage liver diseases (liver failure, cirrhosis, and liver cancer). Over the past 30 years, visionary governments of major nations have provided strong incentives for basic/clinical research, vaccination programmes, and drug discovery and development in the field of hepatology. To get rid of her unflattering title as the "leader in liver diseases", China has also made a serious effort to initiate nationwide preventive measures for liver diseases, global partnerships, and mentoring programmes for young hepatologists. Instrumental to such progress is the continuous support of the National Natural Science Foundation of China (NSFC), which has helped hepatology to thrive in virtually all research directions within the country. In this article, we seek to provide stimulating glimpses into the evolving liver disease epidemiology, institutional research profiles, funding landscape, and drug development trends in China, with an attempt to compare her status and achievements with those of the United States, European countries, and Japan.
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http://dx.doi.org/10.1016/j.jhep.2019.03.004DOI Listing
July 2019

A polyethylenimine-based diazeniumdiolate nitric oxide donor accelerates wound healing.

Biomater Sci 2019 Mar;7(4):1607-1616

College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210093, China.

Nitric oxide (NO) plays a pivotal role in the cutaneous healing process and a topical supplement of NO is beneficial for wound repair. In this work, a novel polyethylenimine (PEI) based diazeniumdiolate nitric oxide donor was prepared. The obtained polymer (PEI-PO-NONOate) was characterized by Fourier transform infrared (FTIR) spectroscopy, UV-vis absorption spectra, and nuclear magnetic resonance (NMR). The PEI-PO-NONOate polymer was stable under anhydrous conditions at different temperatures. A total of 0.57 μmol gaseous NO was released from 1.0 mg of the PEI-PO-NONOate polymer in PBS of pH 7.4 and it presented a proton-driven release pattern. Furthermore, the PEI-PO-NONOate polymer exhibited a controlled release profile sustained for over 30 hours within the polyethylene glycol (PEG) mixture system. Cytotoxicity evaluation was performed on L929 cells. Full-thickness excisional cutaneous wound models of mice were prepared and the PEI-PO-NONOate polymer was applied to investigate its effects on wound healing. The results revealed that the PEI-PO-NONOates exhibited good biocompatibility. It was also found that the PEI-PO-NONOate polymer promoted cutaneous wound healing and closure with enhanced granulation tissue formation, collagen deposition, and angiogenesis, as compared to the control. In summary, a novel nitric oxide releasing polymer with high loading efficiency and a controlled release profile was developed which presented the potential for application in the acceleration of cutaneous wound healing.
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http://dx.doi.org/10.1039/c8bm01519hDOI Listing
March 2019

Three-dimensional nanostructured substrates enable dynamic detection of ALK-rearrangement in circulating tumor cells from treatment-naive patients with stage III/IV lung adenocarcinoma.

J Transl Med 2019 01 18;17(1):32. Epub 2019 Jan 18.

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, People's Republic of China.

Background: Circulating tumor cells (CTC) shows great prospect to realize precision medicine in cancer patients.

Methods: We developed the NanoVelcro Chip integrating three functional mechanisms. NanoVelcro CTC capture efficiency was tested in stage III or IV lung adenocarcinoma. Further, ALK-rearrangement status was examined through fluorescent in situ hybridization in CTCs enriched by NanoVelcro.

Results: NanoVelcro system showed higher CTC-capture efficiency than CellSearch in stage III or IV lung adenocarcinoma. CTC counts obtained by both methods were positively correlated (r = 0.45, p < 0.05). Further, Correlation between CTC counts and pTNM stage determined by NanoVelcro was more significant than that determined by CellSearch (p < 0.001 VS p = 0.029). All ALK-positive patients had 3 or more ALK-rearranged CTC per ml of blood. Less than 3 ALK-rearranged CTC was detected in ALK-negative patients. NanoVelcro can detect the ALK-rearranged status with consistent sensitivity and specificity compared to biopsy test. Furthermore, the ALK-rearranged CTC ratio correlated to the pTNM stage in ALK-positive patients. Following up showed that CTCs counting by NanoVelcro was more stable and reliable in evaluating the efficacy of Clozotinib both in the short and long run compared with CellSearch. Changing of NanoVlecro CTC counts could accurately reflect disease progression.

Conclusion: NanoVelcro provides a sensitive method for CTC counts and characterization in advanced NSCLC. ALK-rearrangement can be detected in CTCs collected from advanced NSCLC patients by NanoVelcro, facilitating diagnostic test and prognosis analysis, most importantly offering one noninvasive method for real-time monitoring of treatment reaction.
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http://dx.doi.org/10.1186/s12967-019-1779-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339314PMC
January 2019

Development and Validation of a Novel Signature to Predict Overall Survival in "Driver Gene-negative" Lung Adenocarcinoma (LUAD): Results of a Multicenter Study.

Clin Cancer Res 2019 03 2;25(5):1546-1556. Epub 2018 Nov 2.

Shen Zhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China.

Purpose: Examining the role of developmental signaling pathways in "driver gene-negative" lung adenocarcinoma (patients with lung adenocarcinoma negative for , and were identified as "driver gene-negative") may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of "driver gene-negative" lung adenocarcinoma.

Experimental Design: In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature.

Results: Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in "driver gene-negative" lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway-based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway-based CSDW signature comprising 4 genes (CTNNB1 or , and ) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46-16.79; < 0.001) than patients with low-risk scores.

Conclusions: The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for "driver gene-negative" lung adenocarcinoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2545DOI Listing
March 2019

Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma.

Int J Cancer 2019 03 26;144(6):1421-1431. Epub 2018 Oct 26.

Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.
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http://dx.doi.org/10.1002/ijc.31742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587450PMC
March 2019

CTHRC1 induces non-small cell lung cancer (NSCLC) invasion through upregulating MMP-7/MMP-9.

BMC Cancer 2018 04 10;18(1):400. Epub 2018 Apr 10.

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, ZhongShan Second Road, Guangdong, 510080, China.

Background: The strong invasive and metastatic nature of non-small cell lung cancer (NSCLC) leads to poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) is involved in cell migration, motility and invasion. The object of this study is to investigate the involvement of CTHRC1 in NSCLC invasion and metastasis.

Methods: A proteomic analysis was performed to identify the different expression proteins between NSCLC and normal tissues. Cell lines stably express CTHRC1, MMP7, MMP9 were established. Invasion and migration were determined by scratch and transwell assays respectively. Clinical correlations of CTHRC1 in a cohort of 230 NSCLC patients were analysed.

Results: CTHRC1 is overexpressed in NSCLC as measured by proteomic analysis. Additionally, CTHRC1 increases tumour cell migration and invasion in vitro. Furthermore, CTHRC1 expression is significantly correlated with matrix metalloproteinase (MMP)7 and MMP9 expression in sera and tumour tissues from NSCLC. The invasion ability mediated by CTHRC1 were mainly MMP7- and MMP9-dependent. MMP7 or MMP9 depletion significantly eradicated the pro-invasive effects mediated by CTHRC1 on NSCLC cells. Clinically, patients with high CTHRC1 expression had poor survival.

Conclusions: CTHRC1 serves as a pro-metastatic gene that contributes to NSCLC invasion and metastasis, which are mediated by upregulated MMP7 and MMP9 expression. Targeting CTHRC1 may be beneficial for inhibiting NSCLC metastasis.
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http://dx.doi.org/10.1186/s12885-018-4317-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891957PMC
April 2018

Mucinous gastric carcinoma: an update of clinicopathologic features and prognostic value from a retrospective study of clinical series.

Int J Clin Exp Pathol 2018 1;11(2):813-821. Epub 2018 Feb 1.

Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University Guangzhou, China.

Mucinous gastric carcinoma (MGC) is a specific type of gastric carcinoma, but its clinicopathologic characteristics remains obscured. Our study aimed to explore clinical features and prognostic value of MGC. This retrospective study included a total of 996 patients with primary gastric carcinoma from June 1994 to December 2006. Patients with gastric carcinoma were divided into MGC, other poorly differentiated (PD), and well or moderately differentiated groups. In all, 68 (6.8%) of 996 patients had MGC, with 599 (60.2%) cases for PD. Our study found that MGC had older age, more distant and peritoneal metastasis, but less radical gastrectomy than PD. Furthermore, the overall survival rate of MGC declined compared with PD gastric cancer (22.3% vs. 28.8%, P=0.032). Younger age (≤60 ys), smaller size (≤5 cm), Bormann III type, and lymph node metastasis were linked to poorer prognosis of MGC. However, MGC itself was not an independent prognostic factor of gastric carcinoma. In conclusion, MGC was associated with poorer prognosis than other types of gastric carcinoma but was not an independent predictive factor for survival, which called for further lucubration of this distinctive type of gastric carcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958002PMC
February 2018

CD155T/TIGIT Signaling Regulates CD8 T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer.

Cancer Res 2017 11 7;77(22):6375-6388. Epub 2017 Sep 7.

Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNγ production, whereas CD155 overexpression inhibited T-cell metabolism and IFNγ production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice. Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0381DOI Listing
November 2017

High Expression of KIF20A Is Associated with Poor Overall Survival and Tumor Progression in Early-Stage Cervical Squamous Cell Carcinoma.

PLoS One 2016 12;11(12):e0167449. Epub 2016 Dec 12.

Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

Background: The kinesin family member 20a (KIF20A) protein has been implicated in the development and progression of many human cancers; however, its precise function and role in cervical cancer remain largely unclear. This study aimed to investigate the expression profile and prognostic value of KIF20A in patients with early-stage cervical squamous cell carcinoma.

Methods: We examined the mRNA and protein levels of KIF20A in eight cervical cancer cell lines and eight paired cervical cancer samples, compared with normal cervical epithelial cells and adjacent normal cervical tissues, respectively. Immunohistochemistry was performed to detect the expression of KIF20A in paraffin-embedded specimens from 169 early-stage cervical squamous cell carcinoma patients. Statistical analyses were applied to analyze the association between KIF20A expression and clinical variables, as well with patient survival.

Results: The mRNA and protein expression levels of KIF20A were significantly elevated in cervical cancer cell lines and lesions compared with normal cells and corresponding normal tissues (P < 0.05). Immunohistochemistry analysis in 169 cervical cancer cases revealed that increased KIF20A expression was strongly associated with human papillomavirus (HPV) infection (P = 0.008), clinical stage (P = 0.001), tumor recurrence (P = 0.016), vital status (P < 0.001), the property of the surgical margin (P = 0.032), the lymphovascular space involvement (P = 0.014), and pelvic lymph node metastasis (P = 0.001). The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression. KIF20A was an independent survival prognostic factor, as evidenced by univariate and multivariate analysis.

Conclusions: Our results illustrate that elevated KIF20A expression correlates with HPV infection, clinical stage, tumor recurrence, lymphovascular space involvement, pelvic lymph node metastasis, and poor outcome in early-stage cervical squamous cell carcinoma patients. KIF20A aberrant expression is a novel independent unfavorable prognostic factor and may present a potential therapeutic target for cervical cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152822PMC
June 2017

Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma.

Int J Oncol 2017 Jan 29;50(1):173-184. Epub 2016 Nov 29.

Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.

TIMELESS is a highly conserved protein required for the maintenance of normal mammalian circadian oscillations and for controlling cellular metabolism and proliferation. Recently, TIMELESS was implicated in the tumorigenesis of certain cancers. However, little is known on TIMELESS protein expression and its potential as a prognostic factor in cervical cancer. Here, we investigate TIMELESS expression pattern and its clinicopathological significance in early-stage cervical carcinoma. TIMELESS mRNA and protein expression was evaluated by real-time PCR and western blot analysis in cervical cancer cell lines, a normal cervical cell line, as well as in six pairs of surgically removed cervical cancer and adjacent normal cervical tissues. A total of 189 paraffin-embedded cervical carcinoma specimens were detected and diagnosed by immunohistochemistry (IHC), and the clinical significance of TIMELESS expression was further analyzed. Aberrant TIMELESS mRNA and protein expression were demonstrated in cervical cancer cell lines compared with the normal cervical cell line. TIMELESS mRNA and protein expression were significantly increased in cervical cancer specimens compared with adjacent non-cancerous cervical specimens. TIMELESS protein expression was significantly associated with the age (P=0.011), clinical stage (P<0.001), pelvic lymph node metastasis (P<0.001), squamous cell carcinoma antigen (P=0.003), tumor recurrence (P=0.015), vital status (P<0.001), tumor differentiation grade (P<0.001), property of the surgical margin (P=0.036) and lymphovascular space involvement (P=0.001). Patients with increased TIMELESS protein expression showed strong tendencies to receive postoperative radiotherapy (P=0.002). Upregulation of TIMELESS correlated with poorer overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox-regression analyses showed that TIMELESS can be regarded as an independent predictive biomarker for poor clinical outcome for early-stage cervical carcinoma. Our results show that TIMELESS overexpression correlates with pelvic lymph node metastasis, lymphovascular space involvement, as well as unfavorable OS and DFS in human cervical cancer. Therefore, TIMELESS expression may be a potential prognostic biomarker for cervical cancer patients.
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http://dx.doi.org/10.3892/ijo.2016.3784DOI Listing
January 2017

Adalimumab for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Meta-Analysis.

BioDrugs 2016 Jun;30(3):207-17

The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.

Background: Evidence-based studies are increasingly being focused on evaluating the efficacy and safety of adalimumab (ADA) for moderately to severely active ulcerative colitis (UC). However, the dosage pattern of ADA for UC management is still not clear.

Objective: A meta-analysis was conducted to evaluate the efficacy and safety of different ADA dosage regimens for moderately to severely active UC.

Methods: The Medline, EMBASE, ISI Web of Knowledge, and Cochrane databases were searched from their inception to January 2015. Randomized controlled trials (RCTs) comparing ADA with placebo were eligible for initial inclusion. The efficacy and side effects were evaluated for ADA 160/80 (ADA 160/80 mg at weeks 0/2 and then 40 mg at weeks 4 and 6), and ADA 80/40 (ADA 80/40 mg at weeks 0/2 and then 40 mg at weeks 4 and 6) induction therapy, with ADA 40 mg every other week (EOW) for maintenance therapy of 52 weeks. The pooled risk ratio (RR) and its 95 % confidence interval (CI) were calculated.

Results: Three RCTs were included. All of the studies were considered to have a low risk of bias. ADA 160/80 was more effective than placebo for induction of clinical remission (RR 1.62, 95 % CI 1.15-2.29), clinical response (RR 1.37, 95 % CI 1.19-1.59), mucosal healing (RR 1.27, 95 % CI 1.08-1.50), and inflammatory bowel disease questionnaire (IBDQ) response (RR 1.22, 95 % CI 1.05-1.43) and did not increase adverse events (RR 1.10, 95 % CI 0.95-1.27). Compared with placebo, ADA 80/40 did not show significant differences for induction of clinical remission and clinical response and did not increase adverse events. ADA 40 mg EOW was superior to placebo in maintaining clinical remission (RR 2.38, 95 % CI 1.57-3.59), clinical response (RR 1.69, 95 % CI 1.29-2.21), mucosal healing (RR 1.69, 95 % CI 1.26-2.28), and IBDQ response (RR 1.73, 95 % CI 1.28-2.34). Compared with placebo, ADA 40 mg EOW increased adverse events (RR 1.28, 95 % CI 1.06-1.54).

Conclusion: ADA 160/80 was a safe and effective treatment for induction management of moderately to severely active UC, but the benefits of ADA 80/40 application were limited. ADA 40 mg EOW was effective for maintenance management of UC. Additional well designed RCTs are needed to confirm these results.
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http://dx.doi.org/10.1007/s40259-016-0173-6DOI Listing
June 2016

L858R-positive lung adenocarcinoma with KRAS G12V, EGFR T790M and EGFR L858R mutations: A case report.

Oncol Lett 2015 Sep 30;10(3):1293-1296. Epub 2015 Jun 30.

Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.

Improvement in the current understanding of the molecular basis of lung cancer at multiple levels, including the genetic, epigenetic and protein levels, has the potential to impact the diagnosis, prognosis and treatment of lung cancer. The mutation status of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is known to be a predictor of the response to gefitinib in lung cancer. Furthermore, mutations in the EGFR and KRAS genes appear to be mutually exclusive. The present study reports a rare case of a patient harboring two EGFR mutations (L858R and T790M) and a KRAS mutation (G12V). The development of gefitinib resistance was detected in the subsequent treatment. The present study indicates that EGFR and KRAS mutational analysis should be recommended for all patients with non-small-cell lung carcinoma.
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http://dx.doi.org/10.3892/ol.2015.3435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533255PMC
September 2015

Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma.

Tumour Biol 2016 May 28;37(5):6239-54. Epub 2015 Nov 28.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Gynecologic Oncology, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and β-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.
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http://dx.doi.org/10.1007/s13277-015-4419-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875171PMC
May 2016

Surgical interventions for gastric cancer: a review of systematic reviews.

Int J Clin Exp Med 2015 15;8(8):13657-69. Epub 2015 Aug 15.

School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center Guangzhou 510006, Guangdong Province, P. R. China.

Aim: To evaluate methodological quality and the extent of concordance among meta-analysis and/or systematic reviews on surgical interventions for gastric cancer (GC).

Methods: A comprehensive search of PubMed, Medline, EMBASE, the Cochrane library and the DARE database was conducted to identify the reviews comparing different surgical interventions for GC prior to April 2014. After applying included criteria, available data were summarized and appraised by the Oxman and Guyatt scale.

Results: Fifty six reviews were included. Forty five reviews (80.4%) were well conducted, with scores of adapted Oxman and Guyatt scale ≥ 14. The reviews differed in criteria for avoiding bias and assessing the validity of the primary studies. Many primary studies displayed major methodological flaws, such as randomization, allocation concealment, and dropouts and withdrawals. According to the concordance assessment, laparoscopy-assisted gastrectomy (LAG) was superior to open gastrectomy, and laparoscopy-assisted distal gastrectomy was superior to open distal gastrectomy in short-term outcomes. However, the concordance regarding other surgical interventions, such as D1 vs. D2 lymphadenectomy, and robotic gastrectomy vs. LAG were absent.

Conclusion: Systematic reviews on surgical interventions for GC displayed relatively high methodological quality. The improvement of methodological quality and reporting was necessary for primary studies. The superiority of laparoscopic over open surgery was demonstrated. But concordance on other surgical interventions was rare, which needed more well-designed RCTs and systematic reviews.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612996PMC
November 2015

Identification and functional annotation of lncRNA genes with hypermethylation in colorectal cancer.

Gene 2015 Nov 11;572(2):259-65. Epub 2015 Jul 11.

Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China. Electronic address:

Colorectal cancer (CRC) is one of the leading causes of mortality worldwide. DNA methylation is an important epigenetic modification for CRC. Although currently a number of studies about DNA methylation of protein coding genes have been carried out, only a few are about the methylation of genes encoding the long noncoding RNAs (lncRNAs). In this study, we identified 761 lncRNA genes with DNA hypermethylation in CRC using a free MethylCap-seq dataset. Integration of lncRNA expression and methylation datasets showed that the expression of lncRNAs is negatively correlated with DNA methylation (p<0.01). Co-methylation network was also constructed to annotate the functions of unknown lncRNAs. Our results showed that a total of 364 lncRNAs were annotated with at least one GO biological process term. The current data-mining work is likely to provide informative clues for biological researchers to further understand the role of lncRNAs in the development of CRC.
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http://dx.doi.org/10.1016/j.gene.2015.07.028DOI Listing
November 2015

SGK3 (CISK) may induce tumor angiogenesis (Hypothesis).

Oncol Lett 2015 Jul 6;10(1):23-26. Epub 2015 May 6.

Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.

Serum- and glucocorticoid-inducible protein kinase 3 (SGK3), also known as cytokine-independent survival kinase (CISK), encoded by chromosome 8q12.2, is a downstream mediator of phosphatidylinositol 3-kinase (PI3K) oncogenic signaling. As a downstream target of PI3K, SGK3 has been reported to mediate pivotal roles in oncogenic progress in various cancers, including breast cancer, ovarian cancer and hepatocellular carcinoma. Functionally parallel to v-akt murine thymoma viral oncogene homolog (AKT)/protein kinase B, SGK3 serves as a hallmark mediating glycogen synthase kinase-β (GSK3-β), B-cell lymphoma (Bcl)-2-associated death promoter, forkead family of transcription factors, Bcl-extra large, Bcl-2, mammalian target of rapamycin, C-X-C chemokine receptor type 4 (CXCR4) and numerous other molecules in cell proliferation, growth, survival, migration and even tumor angiogenesis. Tumor angiogenesis is recognized as an essential step for tumor growth, invasion and metastasis, and it has become an intriguing target for anticancer drug development for tumor investigators worldwide. An abundance of experiments have been performed to investigate the role of the phosphoinositide 3-kinase (PI3K)/AKT pathway in regulating tumor angiogenesis. The mechanism of angiogenesis regulated by the PI3K/AKT pathway is, to a certain extent, clear. Although a number of SGK3 target molecules, including CXCR4 and GSK3β, have demonstrated potential roles in promoting angiogenesis, the exact association between angiogenesis and SGK3 remains unclear. Thus, we hypothesize that SGK3, parallel to AKT, may also be important in mediating angiogenesis. Identifying the role of SGK3 in tumor angiogenesis will certainly present a novel perspective on the malignant transformation of tumors, as well as a target for tumor therapy.
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http://dx.doi.org/10.3892/ol.2015.3182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487054PMC
July 2015

Astrocyte elevated gene-1(AEG-1) induces epithelial-mesenchymal transition in lung cancer through activating Wnt/β-catenin signaling.

BMC Cancer 2015 Mar 8;15:107. Epub 2015 Mar 8.

Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou, Guangdong, 510080, Peoples' Republic of China.

Background: Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited therapeutic options, so development of novel therapies that target NSCLC is needed. During the early stage of metastasis, the cancer cells undergo an epithelial-mesenchymal transition (EMT), a phase in which Wnt/β-catenin signaling is known to be involved. Simultaneously, AEG-1 has been demonstrated to activate Wnt-mediated signaling in some malignant tumors.

Methods: Human NSCLC cell lines and xenograft of NSCLC cells in nude mice were used to investigate the effects of AEG-1 on EMT. EMT or Wnt/β-catenin pathway-related proteins were characterized by western blot, immunofluorescence and immunohistochemistry.

Results: In the present study, we demonstrated that astrocyte elevated gene-1(AEG-1) ectopic overexpression promoted EMT, which resulted from the down-regulation of E-cadherin and up-regulation of Vimentin in lung cancer cell lines and clinical lung cancer specimens. Using an orthotopic xenograft-mouse model, we also observed that AEG-1 overexpression in human carcinoma cells led to the development of multiple lymph node metastases and elevated mesenchymal markers such as Vimentin, which is a characteristic of cells in EMT. Furthermore, AEG-1 functioned as a critical protein in the regulation of EMT by directly targeting multiple positive regulators of the Wnt/β-catenin signaling cascade, including GSK-3β and CKIδ. Notably, overexpression of AEG-1 in metastatic cancer tissues was closely associated with poor survival of NSCLC patients.

Conclusions: These results reveal the critical role of AEG-1 in EMT and suggest that AEG-1 may be a prognostic biomarker and its targeted inhibition may be utilized as a novel therapy for NSCLC.
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http://dx.doi.org/10.1186/s12885-015-1124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358870PMC
March 2015

Proximal gastric cancer: lymph node metastatic patterns according to different T stages dictate surgical approach.

Chin Med J (Engl) 2014 ;127(23):4049-54

Department of Gastrointestinal Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. Email:

Background: As a common form of gastric cancer migration, lymph node metastasis largely affects the surgical treatment and prognosis of gastric cancer. Surgery is the fundamental curative option for gastric cancer that varies depending on different stages. The study aimed to compare the clinicopathological characteristics and lymph node metastatic patterns in patients of proximal gastric cancer with different T stages and investigate a reasonable radical gastrectomy approach in terms of the range of lymphadenectomy for proximal gastric cancer.

Methods: In our retrospective study, the data of 328 patients of proximal gastric cancer with different T stages were analyzed. By comparing the differences of lymph node metastatic rate and ratio, we investigated the clinicopathological characteristics and metastatic patterns of lymph nodes. Also, we were especially interested in the differences in survival rates between patients with and without No. 5 and 6 group metastasis with the same TNM stage.

Results: The overall lymph node metastatic rate and ratio of advanced proximal gastric cancer were 73.4% and 23.3%, respectively. The tumors of different T stages were statistically significant in size and differentiation degree (P < 0.05), multivariate analysis showed that the depth of tumor invasion was an independent risk factor for lymph node metastasis in proximal gastric cancer (RR, 12.025; 95% CI, 2.326 to 62.157; P = 0.003). The overall survival rate of patients with No. 5, 6 group lymph node metastasis and those without was significantly different, but the differences in survival rates between patients with and without No. 5 and 6 group metastasis with the same TNM stage were not statistically significant.

Conclusions: Different T stages in proximal gastric cancer showed different patterns and characteristics of lymph node metastasis. D2 lymphadenectomy in patients with early gastric cancer had little survival benefit because metastasis to level 2 nodes was rare. Therefore the range of the lymph node dissection in radical gastrectomy for early gastric cancer was considered reasonable. Moreover, to meet the requirements of the lymph node dissection, total gastrectomy plus D2 lymphadenectomy or more are supposed to be applied for the advanced proximal gastric cancer patients. Precise T staging largely determines the range of gastrectomy and lymphadenectomy.
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August 2015
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