Publications by authors named "Chengjun Sui"

24 Publications

  • Page 1 of 1

A combined Cox and logistic model provides accurate predictive performance in estimation of time-dependent probabilities for recurrence of intrahepatic cholangiocarcinoma after resection.

Hepatobiliary Surg Nutr 2021 Aug;10(4):464-475

International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.

Background: Intrahepatic cholangiocarcinoma has heterogeneous outcomes after resection. There remains a need for broadly applicable recurrence-specific tool offering precise evaluation on curativeness of resection.

Methods: A four hospital-based clinical cohort involving 1,655 patients with intrahepatic cholangiocarcinoma who received surgical resection were studied. Cox and logistic models were networked into one system containing risk categories with distinctive probabilities of recurrence. Prediction of time-to-recurrence was performed by formulizing time-dependent risk probabilities. The model was validated in three clinical cohorts (n=332).

Results: From the training cohort, 10 and 11 covariates, including diabetes, cholelithiasis, albumin, platelet count, alpha fetoprotein, carbohydrate antigen 19-9, carcinoembryonic antigen, hepatitis B virus infection, tumor size and number, resection type, and lymph node metastasis, from Cox and logistic models were identified significant for recurrence-free survival (RFS). The combined Cox & logistic ranking system (CCLRS)-adjusted time-dependent probabilities were categorized into seven ranks (5-yr RFS for lowest and highest ranks were 75% 0%; hazard ratio 18.5, 95% CI: 14.7-24.9, P<0.0001). The CCLRS was validated with a minimum area under curve value of 0.8086. Prediction of time-to-recurrence was validated to be excellent (Pearson r, 0.8204; P<0.0001).

Conclusions: The CCLRS allows precise estimation on risk of recurrence for intrahepatic cholangiocarcinoma after resection. It could be applicative when estimating time-dependent disease status and stratifying individuals who sole resection of the tumor would not be curative.
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http://dx.doi.org/10.21037/hbsn.2020.01.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351002PMC
August 2021

Discovery of a CPS1-deficient HCC subtype with therapeutic potential via integrative genomic and experimental analysis.

Hepatology 2021 Aug 3. Epub 2021 Aug 3.

The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.

Background And Aims: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack of in-depth study. Here, through analysis of big databases and clinical samples, we identified Carbamoyl phosphate synthetase I(CPS1)-deficient hepatocellular carcinoma(HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as target for HCC prevention.

Approach And Results: Pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas(TCGA) demonstrated that urea cycle(UC) was liver-specific and HCC-downregulated. A large-scale gene expression data analysis including a total of 2,596 HCC cases in 7 HCCDB datasets combined with a total of 17,444 hepatectomy cohort data identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed crucial role of CPS1 in HCC. LC-MS assay and Seahorse analysis revealed that UC dysregulation(UCD) led to the deceleration of the tricarboxylic acid(TCA) cycle, while excess ammonia caused by CPS1 deficiency activated fatty acid β-oxidation(FAO) through p-AMPK. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating FOXM1. Subcutaneous xenograft tumor models and patient-derived organoids(PDOs) were employed to identify that blocking FAO by Eto may provide therapeutic benefit to HCC patients with CPS1-deficiency.

Conclusions: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for novel therapeutic for this type of HCC through targeting FAO.
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http://dx.doi.org/10.1002/hep.32088DOI Listing
August 2021

Impact of metformin use on risk and mortality of hepatocellular carcinoma in diabetes mellitus.

Clin Res Hepatol Gastroenterol 2021 Jul 28:101781. Epub 2021 Jul 28.

Department of Oncology Biotherapy, The Third Affiliated Hospital of Naval Medical University, 201805, Shanghai, China. Electronic address:

Background: The views regarding the associations between metformin use and hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients are divisive. Thus we summarized all available published studies evaluating the relationship between metformin therapy and HCC survival and risk, and aim to conduct an updated meta-analysis study to more accurately clarify the association.

Methods: We searched for articles regarding impact of metformin use on risk and mortality of HCC in DM and published before April 2021 in databases (PubMed and Web of Science). We used STATA 12.0 software to compute odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) to generate a computed effect size and 95% CI.

Results: The present study showed that metformin use was associated with a decreased risk of HCC in DM with a random effects model (OR/RR = 0.59, 95% CI 0.51 to 0.68, I2 = 96.5%, p < 0.001). In addition, the study indicated that metformin use was associated with a decreased all-cause mortality of HCC in DM with a random effects model (HR = 0.74, 95% CI 0.66 to 0.83, I2 = 49.6%, p = 0.037).

Conclusion: In conclusion, our studies support that the use of metformin in DM patients is significantly associated with reduced risk and all-cause mortality of HCC. And more prospective studies focusing on the metformin therapy as a protective factor for HCC are needed to verify the accuracy of the findings.
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http://dx.doi.org/10.1016/j.clinre.2021.101781DOI Listing
July 2021

Falcarindiol Enhances Cisplatin Chemosensitivity of Hepatocellular Carcinoma Down-Regulating the STAT3-Modulated PTTG1 Pathway.

Front Pharmacol 2021 7;12:656697. Epub 2021 May 7.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy globally and the third leading cause of cancer-related death. Chemotherapy is one of the main methods in treating HCC, while recent studies have found that the resistance of HCC to chemotherapeutic drugs reduces the efficacy of the chemotherapy. Falcarindiol (FAD) is a cytotoxic and anti-inflammatory polyacetylenic oxylipin found in food plants of the carrot family (Apiaceae), while its role in HCC remains to be explored. Here, HCC cells (Huh7 and LM3) were treated with FAD at different doses. Cell proliferation was tested by the cell counting kit-8 (CCK-8) method and colony formation assay, while the apoptosis was monitored by flow cytometry. The profiles of apoptosis-related proteins (Bax, bcl2, and Caspase-3), DNA repair proteins (Rad51, BRCA1, and MDC1), and the signal transducer and activator of transcription 3 (STAT3)/Pituitary Tumor Transforming Gene 1 (PTTG1) were verified by western blot (WB) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The interaction between STAT3 and PTTG1 was verified by immunoprecipitation (IP). In addition, a xenograft tumor model was constructed in mice to explore the anti-tumor effects of FAD , and immunohistochemistry (IHC) was performed to count the number of Ki67-stained cells. As a result, FAD inhibited HCC cell proliferation and DNA repair, facilitated their apoptosis, and also enhanced cisplatin (DDP) chemosensitivity. The Combination Index (CI) evaluation showed that FAD and DDP had synergistic effects in repressing HCC cell proliferation. Besides, FAD dampened the STAT3/PTTG1 pathway expression. Further studies revealed that inhibiting STAT3 enhanced the inhibitive effect of FAD on HCC cells, whereas overexpressing PTTG1 attenuated the anti-tumor effect of FAD. Overall, our study illustrated that FAD is a potential anticancer drug and strengthens the chemosensitivity of HCC cells to DDP by inhibiting the STAT3/PTTG1 pathway.
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http://dx.doi.org/10.3389/fphar.2021.656697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138572PMC
May 2021

circFN1 Mediates Sorafenib Resistance of Hepatocellular Carcinoma Cells by Sponging miR-1205 and Regulating E2F1 Expression.

Mol Ther Nucleic Acids 2020 Dec 2;22:421-433. Epub 2020 Sep 2.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China.

In recent years, circular RNAs (circRNAs) have been shown to have critical regulatory roles in the resistance to anti-cancer drugs. However, the contributions of circRNAs to sorafenib resistance in hepatocellular carcinoma (HCC) remain largely unknown. The present study aims to explore the involvement of circFN1 in sorafenib resistance and how circFN1 is associated with the miR-1205/E2F1 pathway, which have been demonstrated to mediate this resistance in HCC cells. We investigated the expression of circRNAs in five paired sorafenib-sensitive HepG2 cells and sorafenib-resistant (SR)-HepG2 cells by microarray analysis. The quantitative real-time PCR analysis was used to investigate the expression pattern of circFN1 in HCC patient tissues and cell lines. Then, the effects of circFN1 on sorafenib resistance, cell proliferation, and apoptosis were assessed in HCC and . In this study, circFN1 was observed to be upregulated in HCC patient tissues and cell lines. Overexpression of circFN1 in HCC was significantly correlated with aggressive characteristics and served as an independent risk factor for overall survival in patients with HCC. Our and data indicated that inhibition of circFN1 enhances the sorafenib sensitivity of HCC cells. Mechanistically, we found that circFN1 could promote the expression of E2F1 by sponging miR-1205. In summary, our study demonstrated that circFN1 contributes to sorafenib resistance by regulating the miR-1205/E2F1 signaling pathway. These results indicate that circFN1 may represent a potentially valuable target for overcoming sorafenib resistance for HCC.
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http://dx.doi.org/10.1016/j.omtn.2020.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533358PMC
December 2020

Trajectory and Functional Analysis of PD-1 CD4CD8 T Cells in Hepatocellular Carcinoma by Single-Cell Cytometry and Transcriptome Sequencing.

Adv Sci (Weinh) 2020 Jul 18;7(13):2000224. Epub 2020 May 18.

National Center for Liver Cancer Shanghai 200438 China.

The spatial heterogeneity of immune microenvironment in hepatocellular carcinoma (HCC) remains elusive. Here, a single-cell study involving 17 432 600 immune cells of 39 matched HCC (T), nontumor (N), and leading-edge (L) specimens by mass cytometry is conducted. The tumor-associated CD4/CD8 double-positive T (DPT) cells are found enriched in L regions with synergetic expression of PD-1/HLA-DR/ICOS/CD45RO and exhibit a higher level of IFN-, TNF-, and PD-1 upon stimulation. The enrichment of DPT and PD-1DPT in L regions indicates favorable prognosis. These tumor-associated DPT cells with similar phenotype are also verified in other tumors and HCC animal models. Single-cell RNA-seq further characterizes the molecular features of DPT cells and uncovers 11 clusters with different cytotoxicity, exhaustion, and activation scores. TCR-based trajectory analysis reveals that tumor-associated DPT clusters share separated ancestries with local CD4 or CD8SPT cells rather than CD3PBMC cells. TCR clones with frequency above 10 are mainly found coexisting in DPT and CD8SPT cells. Specifically, PD-1DPT cluster (TDPT_10) shares the same ancestry with exhausted CD8SPT cluster (TCD8T_2) and shows higher expression similarity and closer pathological location to PD-1CD8 than PD-1CD4T cells. Together, this study systematically characterizes the unique distribution of PD-1DPTs in HCC and puts forward new insights for the function and origin of tumor-associated DPT cells.
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http://dx.doi.org/10.1002/advs.202000224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341083PMC
July 2020

Long Non-Coding RNA SNHG14 Contributes to the Development of Hepatocellular Carcinoma via Sponging miR-217.

Onco Targets Ther 2020 29;13:4865-4876. Epub 2020 May 29.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, People's Republic of China.

Background: Thousands of long non-coding RNAs (lncRNAs) have been functionally verified as crucial regulators of physiological processes and disease progressions, yet their roles in hepatocellular carcinoma (HCC) have not been clearly illuminated.

Methods: We analyzed the expression of lncRNA-SNHG14 in TCGA data via bioinformatic analysis and detected its expression in HCC specimens by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Loss-of-function experiments were used to study the biological function of SNHG14 in HCC cells. RT-qPCR, Western blotting and dual-luciferase reporter assay were carried out to investigate the molecular mechanism of SNHG14 in HCC.

Results: The upregulation of lncRNA-SNHG14 was observed in HCC tissues compared with normal tissues via RT-qPCR and bioinformatic analysis of TCGA data. Silencing of SNHG14 inhibited cell proliferation and induced cell apoptosis in HCC cells. microRNA-217 (miR-217), the tumor-suppressive miRNA in HCC, was predicted and confirmed as a miRNA sponged by SNHG14 in HCC cells. Via downregulation of miR-217, SNHG14 increased the expression of several miR-217-related oncogenes and subsequently activated oncogene-related signaling pathways in HCC cells. In addition, inhibition of miR-217 reversed SNHG14 silencing induced decrease of cell proliferation and increase of cell apoptosis. Their association was verified in the published microarray dataset and the collected HCC samples.

Conclusion: In summary, SNHG14 is involved in the development of HCC via sponging miR-217 and it may be a biomarker for patients with HCC.
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http://dx.doi.org/10.2147/OTT.S244530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269013PMC
May 2020

LncRNA ST8SIA6-AS1 promotes hepatocellular carcinoma cell proliferation and resistance to apoptosis by targeting miR-4656/HDAC11 axis.

Cancer Cell Int 2020 11;20:232. Epub 2020 Jun 11.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, 215001 Suzhou, China.

Background: Dysregulation of long non-coding RNAs (lncRNAs) results in development of human diseases including hepatocellular carcinoma (HCC). Although several HCC related lncRNAs have been reported, the biological functions of many lncRNAs during the development of HCC remains unknown.

Methods: The expression of ST8SIA6-AS1 was studied by realtime PCR (RT-qPCR) and bioinformatic analysis. The biological functions of ST8SIA6-AS1 was examined by CCK-8 assay and flow cytometry analysis. The target of ST8SIA6-AS1 was analyzed by bioinformatic analysis and validated by dual luciferase reporter assay, western blotting and RT-qPCR.

Results: In this study we demonstrated that ST8SIA6-AS1 was an upregulated lncRNA in hepatocellular carcinoma. SiRNA-mediated knockdown of ST8SIA6-AS1 repressed cell proliferation and induced cell apoptosis in HCC cells. Bioinformatic analysis and RT-qPCR further showed that ST8SIA6-AS1 mainly located in cytoplasm. Dual luciferase reporter assay further revealed that ST8SIA6-AS1 interacted with miR-4656 in HCC cells. In addition, HDAC11 was identified as a target gene in HCC cells and ST8SIA6-AS1 could upregulate HDAC11 via sponging miR-4656. Transfection of recombinant HDAC11 partially rescued the inhibition of cell proliferation and increase of cell apoptosis inducing by knockdown of ST8SIA6-AS1.

Conclusion: In conclusion, our findings suggested that ST8SIA6-AS1 was a novel upregulated lncRNA in HCC and could facilitate cell proliferation and resistance to cell apoptosis via sponging miR-4656 and elevation of HDAC11, which might be a promising biomarker for patients with HCC.
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http://dx.doi.org/10.1186/s12935-020-01325-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288512PMC
June 2020

Long noncoding RNA LINC00460 conduces to tumor growth and metastasis of hepatocellular carcinoma through miR-342-3p-dependent AGR2 up-regulation.

Aging (Albany NY) 2020 06 3;12(11):10544-10555. Epub 2020 Jun 3.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215001, China.

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor in the world. It ranks third among cancer-induced deaths worldwide and has the characteristics of high metastasis and high recurrence rate. Long non-coding RNA (LncRNA) LINC00460 is significantly up-regulated in multiple types of cancers and is closely related to the progression of tumors. However, effects of LINC00460 and corresponding regulatory path in HCC are still poorly investigated.In our study, we found that expression of LINC00460 was up-regulated in HCC tissues and cell lines compared with the control. Then we revealed that knockdown of LINC00460 suppressed cell proliferation and cell mobility and induced cell apoptosis in HCC cells. Further study demonstrated that knockdown of LINC00460 suppressed the progression of HCC by elevating the expression of microRNA (miRNA, miR)-342-3p. Besides that, metastasis marker, Anterior gradient homolog 2 (AGR2) was found to be a target of miR-342-3p and overexpression of AGR2 promoted the progression of HCC. Finally, the experiments further verified the anti-tumor effects of LINC00460 / miR-342-3p / AGR2 axis in HCC.The LINC00460 / miR-342-3p / AGR2 axis exerts anti-tumor effect in HCC and , consolidating and expanding the research about targeted gene therapy for early diagnosis and treatment of HCC.
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http://dx.doi.org/10.18632/aging.103278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346032PMC
June 2020

Latent Risk Intrahepatic Cholangiocarcinoma Susceptible to Adjuvant Treatment After Resection: A Clinical Deep Learning Approach.

Front Oncol 2020 19;10:143. Epub 2020 Feb 19.

International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.

Artificial Intelligence (AI) frameworks have emerged as a novel approach in medicine. However, information regarding its applicability and effectiveness in a clinical prognostic factor setting remains unclear. The AI framework was derived from a pooled dataset of intrahepatic cholangiocarcinoma (ICC) patients from three clinical centers ( = 1,421) by applying the TensorFlow deep learning algorithm to Cox-indicated pathologic (four), serologic (six), and etiologic (two) factors; this algorithm was validated using a dataset of ICC patients from an independent clinical center ( = 234). The model was compared to the commonly used staging system (American Joint Committee on Cancer; AJCC) and methodology (Cox regression) by evaluating the brier score (BS), integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under curve (AUC) values. The framework (BS, 0.17; AUC, 0.78) was found to be more accurate than the AJCC stage (BS, 0.48; AUC, 0.60; IDI, 0.29; NRI, 11.85; < 0.001) and the Cox model (BS, 0.49; AUC, 0.70; IDI, 0.46; NRI, 46.11; < 0.001). Furthermore, hazard ratios greater than three were identified in both overall survival (HR; 3.190; 95% confidence interval [CI], 2.150-4.733; < 0.001) and disease-free survival (HR, 3.559; 95% CI, 2.500-5.067; < 0.001) between latent risk and stable groups in validation. In addition, the latent risk subgroup was found to be significantly benefited from adjuvant treatment (HR, 0.459; 95% CI, 0.360-0.586; < 0.001). The AI framework seems promising in the prognostic estimation and stratification of susceptible individuals for adjuvant treatment in patients with ICC after resection. Future prospective validations are needed for the framework to be applied in clinical practice.
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http://dx.doi.org/10.3389/fonc.2020.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042372PMC
February 2020

lncRNA AK054386 Functions as a ceRNA to Sequester miR-199 and Induce Sustained Endoplasmic Reticulum Stress in Hepatic Reperfusion Injury.

Oxid Med Cell Longev 2019 13;2019:8189079. Epub 2019 Nov 13.

Department of Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Hepatic ischemia-reperfusion injury (IRI) is a very complex pathological process that is often associated with liver trauma and surgery, especially liver transplantation surgery. Although endoplasmic reticulum stress (ERS) plays a role in this process, the posttranscriptional regulators and the underlying mechanisms are still unclear. Here, we report that the lncRNA AK054386 was increased in hepatic IRI models. Furthermore, AK054386 can act as a "competing endogenous RNA (ceRNA)" and regulate ERS-related factors by binding and sequestering miR-199, which was shown to inhibit ERS in our previous report. Increased expression of AK054386, which might be mediated by activated NF-B, resulted in sustained ERS and increased cell apoptosis and death in hepatic IRI mouse and cellular models. In contrast, AK054386 inhibition had protective effects on these models. Our data indicate that AK054386 and miR-199 are critical players in hepatic IRI, and we broadened the scope regarding ceRNA mechanisms. We hope that our results will improve the understanding of hepatic IRI and may provide potential therapeutic targets.
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http://dx.doi.org/10.1155/2019/8189079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885273PMC
May 2020

Expression of Programmed Death Ligand 1 Is Associated with the Prognosis of Intrahepatic Cholangiocarcinoma.

Dig Dis Sci 2020 02 13;65(2):480-488. Epub 2019 Aug 13.

Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China.

Background: Programmed death ligand 1 (PD-L1) is expressed in many malignancies and plays a critical role in escape from immune surveillance through inhibition of its receptor programmed death 1. The role of PD-L1 in intrahepatic cholangiocarcinoma (ICC) and mechanisms of its regulation, however, remain largely unknown.

Aims: To analyze the expression and prognostic significance of PD-L1 in ICC and to study the regulatory mechanisms of PD-L1.

Methods: Samples were obtained from 125 patients diagnosed with ICC in the Eastern Hepatobiliary Surgery Hospital from January 2012 to January 2013. The records of each patient were analyzed to examine the relationship between PD-L1 and clinical data. In vitro experiments were performed to investigate the relationship between PD-L1 and the IL-6/mTOR signaling pathway and the feedback mechanism pathway of PD-L1.

Results: Expression of PD-L1 is closely related to tumor vascular invasion, lymphatic metastasis and TNM staging. High PD-L1 expression is closely related to poor prognosis in ICC. Mechanically, IL-6 induces PD-L1 expression through mTOR signaling in ICC cells. In addition, PD-L1 has a negative feedback inhibition effect on AKT signaling.

Conclusions: In summary, high PD-L1 expression was found to be associated with poor prognosis. The IL-6/mTOR pathway upregulates expression of PD-L1, thus promoting tumor invasion, and PD-L1 negatively inhibits the AKT pathway.
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http://dx.doi.org/10.1007/s10620-019-05787-0DOI Listing
February 2020

Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma.

Gut 2019 12 29;68(12):2195-2205. Epub 2019 Jul 29.

Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.

Objective: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.

Design: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.

Results: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).

Conclusion: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.
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http://dx.doi.org/10.1136/gutjnl-2019-318882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872444PMC
December 2019

LncRNA FOXD2-AS1 as a competitive endogenous RNA against miR-150-5p reverses resistance to sorafenib in hepatocellular carcinoma.

J Cell Mol Med 2019 09 18;23(9):6024-6033. Epub 2019 Jun 18.

Department of Hepato-Pancreato-Biliary Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.

The current study elucidated the role of a long non-coding RNA (lncRNA), FOXD2-AS1, in the pathogenesis of hepatocellular carcinoma (HCC) and the regulatory mechanism underlying FOXD2-AS1/miR-150-5p/transmembrane protein 9 (TMEM9) signalling in HCC. Microarray analysis was used for preliminary screening of candidate lncRNAs in HCC tissues. qRT-PCR and Western blot analyses were used to detect the expression of FOXD2-AS1. Cell proliferation assays, luciferase assay and RNA immunoprecipitation were performed to examine the mechanism by which FOXD2-AS1 mediates sorafenib resistance in HCC cells. FOXD2-AS1 and TMEM9 were significantly decreased and miR-150-5p was increased in SR-HepG2 and SR-HUH7 cells compared with control parental cells. Overexpression of FOXD2-AS1 increased TMEM9 expression and overcame the resistance of SR-HepG2 and SR-HUH7 cells. Conversely, knockdown of FOXD2-AS1 decreased TMEM9 expression and increased the sensitivity of HepG2 and Huh7 cells to sorafenib. Our data also demonstrated that FOXD2-AS1 functioned as a sponge for miR-150-5p to modulate TMEM9 expression. Taken together, our findings revealed that FOXD2-AS1 is an important regulator of TMEM9 and contributed to sorafenib resistance. Thus, FOXD2-AS1 may serve as a therapeutic target against sorafenib resistance in HCC.
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http://dx.doi.org/10.1111/jcmm.14465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714507PMC
September 2019

PEG10 is imperative for TGF-β1-induced epithelial‑mesenchymal transition in hepatocellular carcinoma.

Oncol Rep 2017 Jan 29;37(1):510-518. Epub 2016 Nov 29.

Department of Special Medical Care Ⅰ and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, P.R. China.

Substantial evidence indicates that transforming growth factor-beta 1 (TGF-β1) plays a vital role in epithelial-mesenchymal transition (EMT). PEG10 has been shown involved in invasion and metastasis of tumors. The present study investigated the role of PEG10 in TGF-β1-triggered EMT in hepatocellular carcinoma (HCC) progression. Immunohistochemistry and real-time PCR were used to measure the expression level of PEG10 in clinical HCC tissues with or without lymph node metastasis, and normal tissues. The results showed that PEG10 expression is higher in HCC tissues and associated with overall survival (OS) and lymph node metastasis. Moreover, PEG10 expression level was remarkably higher in hepatic cancer cells than the normal hepatic cell line L02. In the present study, we constructed an adenovirus vector containing the coding area of PEG10 (Ad-PEG10) and infected HepG2 cells and found that overexpression of PEG10 promoted the cell migration, invasion ability and EMT of HepG2 cells. TGF-β1 acted on HepG2 cells by enhancing cell migration, invasion, EMT and upregulating PEG10 expression level. However, cells pretreated with adenovirus vector of PEG10 shRNAs (Ad-shRNA1 and Ad-shRNA2) did not occur EMT prior to TGF-β1 stimulation. Moreover, TGF-β1 did not increase the migration and invasion of cells with PEG10 knockdown and overexpression of PEG10 confers chemoresistance to HepG2 cells. Accordingly, sufficient PEG10 expression level is essential for TGF-β1 induced EMT and associated with the chemoresistance in HepG2 cells.
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http://dx.doi.org/10.3892/or.2016.5282DOI Listing
January 2017

Potential Role of MicroRNA-210 as Biomarker in Human Cancers Detection: A Meta-Analysis.

Biomed Res Int 2015 13;2015:303987. Epub 2015 Sep 13.

Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225, Changhai Road, Shanghai 200438, China.

We conducted this meta-analysis aimed to evaluate diagnostic accuracy of miR-210 in human cancers. A total of 673 cancer patients and 606 cancer-free individuals from 13 studies were contained in this meta-analysis. The overall diagnostic results in our study showed that the pooled sensitivity was 0.70, specificity was 0.76, and the AUC was 0.80. In addition, the PLR and NLR were 2.9 and 0.39, with DOR of 8. After the outliner exclusion detected by sensitivity analysis, these parameters had minimal change, which confirmed the stability of our work. The results in our studies showed that the miR-210 assay yielded relatively moderate accuracy in cancer patients and cancer-free individual differentiation. More basic researches are needed to highlight its role as supplement in clinical treatment.
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http://dx.doi.org/10.1155/2015/303987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584045PMC
June 2016

MiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial-mesenchymal transition.

Cancer Lett 2015 Aug 27;364(1):33-43. Epub 2015 Apr 27.

National Center for Liver Cancer, Shanghai, China; Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200441, China. Electronic address:

Epigenetic modification of miR-429 can manipulate liver T-ICs via targeting the RBBP4/E2F1/Oct4 axis, which might be crucial for hepatocarcinogenesis. However, whether miR-429 plays a role in regulating metastasis of hepatocellular carcinoma is still unclear. Using quantitative methylation analysis and real-time PCR, we have identified the hypomethylated status and upregulation of miR-429 in portal vein metastasis samples in comparison with their matched primary tumor. The ectopic expression of miR-429 dramatically induced the expression of MMP2/7/9 and enhanced HCC migration and invasion in vitro and in vivo in an EMT-independent manner. Both bioinformatics and functional studies elucidated the direct regulation of miR-429 on the 3'UTR of the PTEN gene, which leads to the activation of PI3K/AKT signaling and the nuclear translocation of β-catenin, eventually. Conversely, the knockdown of miR-429 efficiently recovered the expression of PTEN and attenuated PI3K/AKT/β-catenin-mediated cell metastasis. Clinically, the higher expression of miR-429 and nucleus relocation of β-catenin were identified as the adverse prognosis factors for recurrence-free survival (RFS) and overall survival (OS). In summary, our results here defined miR-429 as a key inducer for HCC pathogenesis and metastasis with potential utility for tumor intervention.
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http://dx.doi.org/10.1016/j.canlet.2015.04.023DOI Listing
August 2015

Investigation of serum lncRNA-uc003wbd and lncRNA-AF085935 expression profile in patients with hepatocellular carcinoma and HBV.

Tumour Biol 2015 May 14;36(5):3231-6. Epub 2014 Dec 14.

The Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No.225, Changhai Road, Shanghai, 200438, China.

Hepatocellular carcinoma (HCC) was among the most common solid tumors which rated third in cancer-related mortality worldwide. Hepatitis B viral (HBV) infection represents an important risk factor for HCC. Long non-coding RNAs (lncRNAs) were a class of newfound non-coding RNAs widely depicted in the genome currently. Nevertheless, the potential roles of them in human cancers were not well comprehended. Through this study, we aimed at exploring the expression profile and the potential clinical value of two lncRNAs (lncRNA-uc003wbd and lncRNA-AF085935) in differentiating HCC from both HBV patients and the healthy specimens. Serum samples were extracted from 104 HBV patients, 137 HCC patients, and 138 healthy controls. The lncRNA levels of all the subjects were assayed by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). We differentiated the three groups by the receiver operating characteristic (ROC) curve of each group. Statistical analyses were conducted by GraphPad software. Two-tailed P value less than 0.05 was considered to be statistically significant. The level of serum lncRNA-uc003wbd and lncRNA-AF085935 was significantly upregulated in HCC patients and HBV patients compared with that in normal controls. LncRNA-AF085935 showed a relatively higher accuracy for HCC screening (area under the curve (AUC) = 0.96, 95 % confidence interval (CI) = 0.93-0.99) than lncRNA-uc003wbd (AUC = 0.86, 95 % CI = 0.82-0.91) from healthy controls, as well as for HCC screening (AUC = 0.86, 95 % CI = 0.80-0.91) which is more accurate than lncRNA-uc003wbd (AUC = 0.70, 95 % CI = 0.63-0.76) from HBV patients. When differentiating HBV patients from the normal group, the descriptive value of lncRNA-AF085935 (AUC = 0.77, 95 % CI = 0.71-0.83) was almost as equal to lncRNA-uc003wbd (AUC = 0.76, 95 % CI = 0.70-0.82). In addition, higher expressions of lncRNAs were observed in HCC patients than in HBV patients. LncRNA-uc003wbd and lncRNA-AF085935 were observed with an aberrant serum level in HCC and HBV patients, which is showing that both lncRNA-uc003wbd and lncRNA-AF085935 are able to be potential biomarkers for HCC and HBV screening.
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http://dx.doi.org/10.1007/s13277-014-2951-4DOI Listing
May 2015

Overexpression of miR-218 inhibits hepatocellular carcinoma cell growth through RET.

Tumour Biol 2015 Mar 6;36(3):1511-8. Epub 2014 Nov 6.

Department of Special Medical Care and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with poor prognosis. Here, we investigated the role of microRNA 218 (miR-218) in regulating human HCC development. Quantitative PCR (qPCR) was used to compare the expression levels of miR-218 between eight HCC and a normal liver cell lines, as well as nine primary HCC tissues and adjacent non-carcinoma tissues. HCC cell lines MHCC97L and Huh7 were transfected with lentiviral vector of miR-218 mimics. The effect of miR-218 overexpression on cancer cell growth, both in vitro and in vivo, as well as cancer cell invasion was examined. A bioinformatic method was used to predict the binding of miR-218 to RET proto-oncogene (RET). Small interfering RNA (SiRNA)-mediated genetic knock-down of RET was performed in MHCC97L and Huh7 cells, and its modulatory effect on miR-218-mediated HCC development was examined. miR-218 was found to be downregulated in HCC cell lines and primary HCC tissues. Overexpression of miR-218 in MHCC97L or Huh7 cells resulted in significant decrease in cell proliferation and invasion capability. Overexpression of miR-218 also reduced the tumor growth of xenografted Huh7 cells in vivo. The expression of endogenous RET was found to be upregulated by miR-218, and siRNA-induced RET downregulation resulted in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) upregulation and reversal of the inhibitory effect of miR-218 upregulation on HCC proliferation. Our results indicate that miR-218 modulates HCC development, and this effect may be through RET and PTEN.
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http://dx.doi.org/10.1007/s13277-014-2679-1DOI Listing
March 2015

Methylation patterns of estrogen receptor α promoter correlate with estrogen receptor α expression and clinicopathological factors in hepatocellular carcinoma.

Exp Biol Med (Maywood) 2014 Jul 17;239(7):883-890. Epub 2014 Jun 17.

The Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China

Hepatocellular carcinoma (HCC) is the seventh most common type of cancer; notably, the incidence of HCC is four to eight times higher in men than women. Previous studies reported that the estrogen receptor (ER) signaling pathway is involved in the pathogenesis of HCC, although the extent of its involvement is unclear due to several conflicting reports. In the present study, tumor and paired adjacent non-cancerous tissues from 157 HCC patients were collected. Transcriptome sequencing and real-time quantitative polymerase chain reaction were used to quantify the ER α (ESR1) expression levels, and the Sequenom EpiTYPER assay was used to delineate the methylation patterns in the ESR1 promoter. We found that ESR1 expression was significantly reduced in tumor tissues (P < 0.001) compared to adjacent non-cancerous tissues. The CpG sites around the transcription start site were significantly hypermethylated in the tumor (P < 0.0001). This methylation pattern also correlated with the gene expression (P < 0.0001). Additionally, we found that the hypermethylation of ESR1 was associated with the presence of fibrous capsules (P = 1.2 × 10), the absence of microvascular invasions (P = 8.0 × 10), thin trabecular pattern (P = 0.025), and lower histologic gradings (P = 5.2 × 10). Thus, ESR1 expression is a candidate tumor suppressor gene in HCC. Further, promoter hypermethylation may be a mechanism by which expression of ESR1 is repressed, and the extent of hypermethylation of ESR1 may be a marker for HCC status and progression.
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http://dx.doi.org/10.1177/1535370214536651DOI Listing
July 2014

Infrahepatic inferior vena cava clamping in hepatectomy for tumors involving hepatocaval confluence.

Asian J Surg 2013 Jul 16;36(3):111-5. Epub 2013 Mar 16.

Department of Special Treatment and Liver Transplantation, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Background: Massive hemorrhage and the need for blood transfusion carry a high rate of morbidity and mortality after hepatectomy. The aim of this study was to evaluate the safety and potential benefit of infrahepatic inferior vena cava (IVC) clamping in hepatectomy for tumors involving hepatocaval confluence.

Methods: We conducted a retrospective analysis of 113 consecutive patients who underwent hepatectomy with infrahepatic IVC clamping (n = 60, Group A) and without infrahepatic IVC clamping (n = 53, Group B) as the initial treatment for tumors involving hepatocaval confluence.

Results: In Group A, central venous pressure reduced from 7.6 ± 3.2 to 4.4 ± 2.7 cm H₂O (p < 0.001). Patients in Group A experienced less blood loss (477.3 ± 340.3 vs. 794.5 ± 602.7 mL, p = 0.001), fewer blood transfusion requirements (8.3% vs. 22.6%, p = 0.034), lower postoperative complications (40% vs. 60.4%, p = 0.031), and shorter hospital stay (10.7 ± 2.2 vs. 12.9 ± 4.8 days, p = 0.008) than those in Group B.

Conclusion: Infrahepatic IVC clamping is generally effective and safe in controlling bleeding during hepatectomy for tumors involving hepatocaval confluence.
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http://dx.doi.org/10.1016/j.asjsur.2013.01.002DOI Listing
July 2013

Safety and efficacy of trisectionectomy for hepatocellular carcinoma.

ANZ J Surg 2011 Dec 7;81(12):895-9. Epub 2011 Jan 7.

Department of Hepato-Biliary-Pancreato-Vascular Surgery, The First Affiliated Hospital of Xiamen University, China.

Background: Right or left trisectionectomy represents the most extensive and difficult type of hepatic resection, and carries an unfavourably high morbidity and mortality. This retrospective study aimed to evaluate the safety and efficacy of trisectionectomy for hepatocellular carcinoma (HCC).

Methods: From January 2000 to December 2008, 35 patients with HCC were treated with trisectionectomy. The treatment outcomes of these patients were retrospectively analysed.

Results: Twenty-three right and 12 left trisectionectomies were performed. The overall operative morbidity and mortality were 42.8% (n= 15) and 2.8% (n= 1), respectively. The 1-, 3-, and 5-year overall survival rates were 82.9%, 51.4% and 23.8%, while the 1-, 3- and 5-year disease-free survival rates were 71.4%, 42.9% and 12.9%, respectively.

Conclusions: With careful patient selection and meticulous surgical technique, trisectionectomy can be performed safely and is associated with long-term survival in a subset of patients with HCC.
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http://dx.doi.org/10.1111/j.1445-2197.2010.05605.xDOI Listing
December 2011

Surgical outcome of hepatocellular carcinoma patients with biliary tumor thrombi.

World J Surg Oncol 2011 Jan 8;9. Epub 2011 Jan 8.

Department of Hepato-Biliary-Pancreato-Vascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, PR China.

Background: To investigate the surgical outcome of hepatocellular carcinoma (HCC) patients with biliary tumor thrombi (BTT).

Methods: Surgical outcome of 27 HCC patients with BTT (group I) were compared with randomly selected HCC patients without BTT (group II; n = 270).

Results: One patient in group I died of hepatic failure within 30 days after resection. The 1-, 3- and 5-year cumulative survival rates of group I were 70.3%, 25.9%, and 7.4%, respectively; these were significantly lower than those of group II (90.6%, 54.0%, and 37.7%) (P <0.001). The rates of early recurrence (≤ 1 year) after resection were significantly higher in group I than group II (70.3% vs. 34.8%) (P < 0.001).

Conclusion: HCC patients with BTT had a worse prognosis after resection than those without BTT. Resection should be considered for these tumors given the lack of effective alternative therapies.
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http://dx.doi.org/10.1186/1477-7819-9-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022747PMC
January 2011

Repeat hepatectomy for recurrent hepatocellular carcinoma: a local experience and a systematic review.

World J Surg Oncol 2010 Jul 1;8:55. Epub 2010 Jul 1.

Department of Hepato-Biliary-Pancreato-Vascular Surgery, the First affiliated Hospital of Xiamen University, Xiamen, China.

Background: This study aimed to assess the efficacy and safety of repeat hepatectomy for recurrent hepatocellular carcinoma (HCC).

Methods: Thirty-seven patients who underwent a curative repeat hepatectomy in our hospital were retrospectively studied. An extensive database literature search was performed to obtain for all relevant studies.

Results: In our series, there were no perioperative deaths during repeat hepatectomy for recurrent HCC. Patients survival after repeat hepatectomy were similar to 429 patients undergoing initial hepatectomy. A computerized search of the Medline and PubMed databases found 29 retrospective studies providing relevant data in 1149 patients were included for appraisal and data extraction. After the repeat hepatectomy, postoperative morbidity ranged from 6.2% to 68.2% with a median per cohort of 23.5 per cent. There were 7 perioperative deaths (0.7 per cent of 993 for whom mortality data were provided). The overall median survival ranged from 21 to 61.5 months, with 1-, 3-, and 5-year survival of 69.0% to 100%, 21.0% to 87.0%, and 25.0% to 87.0%, respectively.

Conclusions: Repeat hepatectomy can be performed safely and is associated with long-term survival in a subset of patients with recurrent HCC. However, the findings have to be carefully interpreted due to the lower level of evidence. A randomized controlled study is needed to compare repeat hepatectomy and other modalities for recurrent HCC.
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http://dx.doi.org/10.1186/1477-7819-8-55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904292PMC
July 2010
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