Publications by authors named "Qiuran Xu"

53 Publications

Repression of the miR-627-5p by histone deacetylase 3 contributes to hypoxia-induced hepatocellular carcinoma progression.

J Cancer 2021 3;12(17):5320-5330. Epub 2021 Jul 3.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Hepatocellular carcinoma (HCC) is one of the most common solid tumors globally. Our previous studies revealed that miR-627-5p suppresses HCC progression via targeting BCL3/CCND1 pathway. However, the molecular mechanism by which miR-627-5p was downregulated in HCC remains to be further elucidated. As a hallmark of solid tumors, hypoxia results in the rapid growth, strongly potential invasion and high frequent metastasis of cancer cells. Hypoxia-inducible factors (HIFs), mainly including HIF-1 and HIF-2, are the classical transcription factors which mediate hypoxia-related gene transcription. Here, we demonstrated that miR-627-5p was repressed by hypoxia in a HIF-1-dependent manner in HCC cells. But HIF-1 regulated miR-627-5p expression not directly through the hypoxia-response element (HRE) sites of MIR627 gene. In contrast, histone deacetylase 3 (HDAC3) was identified as a HIF-1 target gene, and the occupancy of HIF-1 to HRE site was essential for hypoxia-mediated HDAC3 induction. And upregulated HDAC3 was closely related to the malignant clinical and pathological characteristics and worse prognosis of HCC. Furthermore, HDAC3-mediated histone deacetylation in promoter region of MIR627 was critical for hypoxia-mediated miR-627-5p repression. And miR-627-5p mediated the effects of hypoxic condition on HCC progression. Thus, this study has revealed that miR-627-5p was repressed by hypoxia under the mediation of HDAC3 in HCC, and there existed a HIF-1α/HDAC3/miR-627-5p/BCL3/CCND1 signal pathway in HCC.
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http://dx.doi.org/10.7150/jca.58697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317525PMC
July 2021

A novel disease-associated nucleic acid sensing platform based on split DNA-scaffolded sliver nanocluster.

Anal Chim Acta 2021 Aug 7;1175:338734. Epub 2021 Jun 7.

School of Basic Medical Sciences, Xi'an Key Laboratory of Immune Related Diseases, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, 710061, China. Electronic address:

Disease-associated nucleic acids, such as DNAs and miRNAs, are important biomarkers for the diagnosis, prognosis and treatment guidance of human diseases. Therefore, the accurate and sensitive detection of nucleic acid is of great significance for the early diagnosis of diseases. DNA-scaffolded silver nanocluster (DNA-Ag NC) is a new type of probe with good photostability and low toxicity that has been widely used in biomedical analysis. In this work, a new universal sensing platform based on target triggered labeling luminescent DNA-Ag NC for disease-related nucleic acids detection was constructed. The assembled split DNA fragment pair (CACT and CGT) could be used as a template to develop a bright green fluorescent Ag NC. According to this phenomenon, we devised two probe sequences DNA 1 and DNA 2, which could hybridize to the same one target and contained a different split fragment of Ag NC' scaffold. The target compelled the split fragments close to each other through base pairing with DNA 1 and DNA 2, thus quantification of the target could be achieved through measuring green fluorescence of Ag NC that produced by assembled scaffold in ternary hybrid products. We applied this platform successfully for miR-362, a potential biomarker of inflammatory bowel diseases (IBD), or HIV-related DNA (hDNA) detection, achieving the detection limits of 6.5 nM and 1.7 nM, respectively. Both of the assays showed excellent reproducibility, selectivity and potential applications in human serum samples. In summary, an economic and convenient universal platform was developed for disease-associated nucleic acid detection.
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http://dx.doi.org/10.1016/j.aca.2021.338734DOI Listing
August 2021

Effect of the Hypoxia Inducible Factor on Sorafenib Resistance of Hepatocellular Carcinoma.

Front Oncol 2021 7;11:641522. Epub 2021 Jul 7.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

Sorafenib a multi-target tyrosine kinase inhibitor, is the first-line drug for treating advanced hepatocellular carcinoma (HCC). Mechanistically, it suppresses tumor angiogenesis, cell proliferation and promotes apoptosis. Although sorafenib effectively prolongs median survival rates of patients with advanced HCC, its efficacy is limited by drug resistance in some patients. In HCC, this resistance is attributed to multiple complex mechanisms. Previous clinical data has shown that HIFs expression is a predictor of poor prognosis, with further evidence demonstrating that a combination of sorafenib and HIFs-targeted therapy or HIFs inhibitors can overcome HCC sorafenib resistance. Here, we describe the molecular mechanism underlying sorafenib resistance in HCC patients, and highlight the impact of hypoxia microenvironment on sorafenib resistance.
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http://dx.doi.org/10.3389/fonc.2021.641522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292964PMC
July 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 8;17(9):2336-2337. Epub 2021 Jun 8.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241735PMC
June 2021

HIF-1α-activated TM4SF1-AS1 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by enhancing TM4SF1 expression.

Biochem Biophys Res Commun 2021 Aug 10;566:80-86. Epub 2021 Jun 10.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. Electronic address:

Long non-coding RNAs (lncRNAs) are essential drivers or suppressors in human hepatocellular carcinoma (HCC) by participating in controlling transcription, translation, mRNA stability, and protein degradation protein-protein interaction. TM4SF1-AS1 is recently identified as a tumor-promoting factor in lung cancer. Nevertheless, its function in HCC and related molecular mechanisms remain unknown. Here, our data indicated that either hypoxia or hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (DMOG) induced the upregulation of TM4SF1-AS1 in HCC cells. HIF-1α knockdown rather than HIF-2α silencing remarkably abrogated hypoxia-upregulated TM4SF1-AS1 expression. Furthermore, we confirmed the elevated expression of TM4SF1-AS1 in HCC tissue samples and cell lines. The silencing of TM4SF1-AS1 prominently inhibited the proliferative, migratory, and invasive abilities of HCC cells. TM4SF1-AS1 depletion significantly blocked hypoxia-enhanced Hep3B cell proliferation and mobility. Interfering TM4SF1-AS1 remarkably reduced TM4SF1 mRNA and protein levels in HCC cells. But TM4SF1-AS1 knockdown did not impact the stability of TM4SF1 mRNA. Hypoxia enhanced the expression of TM4SF1 mRNA, which was subsequently decreased by TM4SF1-AS1 knockdown in HCC cells. We confirmed the positive correlation between TM4SF1 mRNA and TM4SF1-AS1 expression in HCC specimens. Finally, TM4SF1 prominently reversed the inhibitory role of TM4SF1-AS1 depletion in Hep3B cells. In summary, hypoxia-responsive TM4SF1-AS1 was overexpressed in human HCC and contributed to the malignant behaviors of tumor cells by enhancing TM4SF1-AS1 expression.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.011DOI Listing
August 2021

Long noncoding RNA FIRRE contributes to the proliferation and glycolysis of hepatocellular carcinoma cells by enhancing PFKFB4 expression.

J Cancer 2021 13;12(13):4099-4108. Epub 2021 May 13.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Recent reports show that long noncoding RNA (lncRNA) FIRRE contributes to the proliferation, apoptosis resistance, and invasion of colorectal cancer and diffuse large B-cell lymphoma. However, the biological function of FIRRE in hepatocellular carcinoma (HCC) remains unknown. Here, we disclosed that the FIRRE level was frequently increased in HCC compared to nontumor tissues. Compared with normal liver cells, we also confirmed the upregulated level of FIRRE in HCC cells. Notably, the FIRRE high expression was related to malignant clinical features, including advanced TNM stage and tumor size ≥5 cm, and conferred to worse survival of HCC. Functionally, FIRRE knockdown repressed the proliferation and glycolysis of HCCLM3 cells. Overexpression of FIRRE strengthened Huh7 cell proliferation and glycolysis. Notably, FIRRE positively regulated the glycolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression in HCC cells. PFKFB4 was highly expressed and positively associated with FIRRE level in HCC tissues. The upregulated expression of PFKFB4 was associated with high tumor grade and advanced TNM stage. TCGA data revealed that the PFKFB4 high expression indicated a poor prognosis of HCC. Mechanistically, modulating FIRRE level did not affect the stability of PFKFB4 mRNA. FIRRE was mainly distributed in HCC cells' nucleus and promoted PFKFB4 transcription and expression via cAMP-responsive element-binding protein (CREB). PFKFB4 could abolish the effects of FIRRE knockdown on HCC cell proliferation and glycolysis. To conclude, the highly expressed FIRRE facilitated HCC cell proliferation and glycolysis by enhancing CREB-mediated PFKFB4 transcription and expression.
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http://dx.doi.org/10.7150/jca.58097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176253PMC
May 2021

Erratum: Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis: Erratum.

Int J Biol Sci 2021 20;17(7):1742-1743. Epub 2021 Apr 20.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

[This corrects the article DOI: 10.7150/ijbs.45457.].
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http://dx.doi.org/10.7150/ijbs.61130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120462PMC
April 2021

[Corrigendum] MicroRNA‑122 affects cell aggressiveness and apoptosis by targeting PKM2 in human hepatocellular carcinoma.

Oncol Rep 2021 Jul 13;46(1). Epub 2021 May 13.

Department of Neurosurgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.

Following the publication of the above article, an interested reader drew to the authors' attention that Figs. 6C and 7A apparently contained overlapping panels, suggesting that these data for purportedly different experiments had been derived from the same original source. The wound‑healing result for the anti‑miR‑122+siRNA PKM2 experiment in the lower panel of Fig. 6C and the transwell invasion result for the anti‑miR‑122+siRNA PKM2 experiment in Fig. 7A were erroneously selected. Accordingly, the authors repeated these assays and were able to confirm that the results were in accordance with the published results. Consequently, the corrected versions of Figs. 6 and 7, containing the replacement data for Figs. 6C and 7A, are shown opposite. It should be emphasized that the inadvertent errors that occurred during the compilation of these figures did not affect the research results or the conclusions of this article. The authors all agree to this Corrigendum, and are grateful to the Editor of for allowing them to have the opportunity to correct these errors. The authors also apologize to the readership for any inconvenience these errors may have caused. [the original article was published in 34: 2054‑2064, 2015; DOI: 10.3892/or.2015.4175].
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http://dx.doi.org/10.3892/or.2021.8073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129967PMC
July 2021

Identification and validation of redox-immune based prognostic signature for hepatocellular carcinoma.

Int J Med Sci 2021 10;18(9):2030-2041. Epub 2021 Mar 10.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

The intimate interaction between redox signaling and immunity has been widely revealed. However, the clinical application of relevant therapeutic is unavailable due to the absence of validated markers that stratify patients. Here, we identified novel biomarkers for prognosis prediction in hepatocellular carcinoma (HCC). Prognostic redox-immune-related genes for predicting overall survival (OS) of HCC were identified using datasets from TCGA, LIRI-JP, and GSE14520. LASSO Cox regression was employed to construct the signature model and generate a risk score in the TCGA cohort. The signature contained CDO1, G6PD, LDHA, GPD1L, PPARG, FABP4, CCL20, SPP1, RORC, HDAC1, STC2, HDGF, EPO, and IL18RAP. Patients in the high-risk group had a poor prognosis compared to the low-risk group. Univariate and multivariate Cox regressions identified this signature as an independent factor for predicting OS. Nomogram constructed by multiple clinical parameters showed good performance for predicting OS indicated by the c-index, the calibration curve, and AUC. GSEA showed that oxidoreductase activity and peroxisome-related metabolic pathways were enriched in the low-risk group, while glycolysis activity and hypoxia were higher in the high-risk group. Furthermore, immune profiles analysis showed that the immune score and stromal score were significantly decreased in the high-risk group in the TCGA cohort. There was a considerably lower infiltration of anti-tumor immune cells while a higher proportion of pro-tumor immune cells in silico. Immune markers were distinctly expressed between the subgroups, and redox-sensitive immunoregulatory biomarkers were at higher levels in the high-risk group. Altogether, we identified a redox-immune prognostic signature. A more severe redox perturbation-driven immunosuppressive environment in the high-risk group stratified by the signature may account for poor survival. This may provide a clue to the combined therapy targeting redox and immune in HCC.
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http://dx.doi.org/10.7150/ijms.56289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040390PMC
March 2021

Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies.

J Immunol Res 2021 22;2021:8816041. Epub 2021 Jan 22.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Autoimmune diseases (such as rheumatoid arthritis, asthma, autoimmune bowel disease) are a complex disease. Improper activation of the immune system or imbalance of immune cells can cause the immune system to transform into a proinflammatory state, leading to autoimmune pathological damage. Recent studies have shown that autoimmune diseases are closely related to CD4+ T helper cells (Th). The original CD4 T cells will differentiate into different T helper (Th) subgroups after activation. According to their cytokines, the types of Th cells are different to produce lineage-specific cytokines, which play a role in autoimmune homeostasis. When Th differentiation and its cytokines are not regulated, it will induce autoimmune inflammation. Autoimmune bowel disease (IBD) is an autoimmune disease of unknown cause. Current research shows that its pathogenesis is closely related to Th17 cells. This article reviews the role and plasticity of the upstream and downstream cytokines and signaling pathways of Th17 cells in the occurrence and development of autoimmune bowel disease and summarizes the new progress of IBD immunotherapy.
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http://dx.doi.org/10.1155/2021/8816041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846404PMC
January 2021

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma.

Front Cell Dev Biol 2020 19;8:587389. Epub 2020 Oct 19.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The activation of the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB (TLR4/MyD88/NF-κB) pathway contributes to the development and progression of HCC. The ubiquitin-proteasome system regulates TLR4 expression. However, whether ubiquitin specific peptidase 13 (USP13) stabilizes TLR4 and facilitates HCC progression remains unclear. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry analysis revealed that USP13 expression in HCC tissues was higher than in non-tumor liver tissues. Moreover, the elevated expression of USP13 was detected in HCC cells (SK-HEP-1, HepG2, Huh7, and Hep3B) compared to LO2 cells. Interestingly, the positive staining of USP13 was closely correlated with tumor size ≥ 5 cm and advanced tumor stage and conferred to significantly lower survival of HCC patients. Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells. The silencing of USP13 significantly restrained the growth and lung metastasis of HCC cells . Mechanistically, the USP13 depletion markedly inhibited the TLR4/MyD88/NF-κB pathway in HCC cells. USP13 interacted with TLR4 and inhibited the ubiquitin-mediated degradation of TLR4. Significantly, TLR4 re-expression remarkably reversed the effects of USP13 knockdown on HCC cells. USP13 expression was markedly upregulated in HCC cells under hypoxia conditions. Notably, USP13 knockdown repressed hypoxia-induced activation of the TLR4/MyD88/NF-κB pathway in HCC cells. In conclusion, our study uncovered that hypoxia-induced USP13 facilitated HCC progression via enhancing TLR4 deubiquitination and subsequently activating the TLR4/MyD88/NF-κB pathway.
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http://dx.doi.org/10.3389/fcell.2020.587389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604352PMC
October 2020

TGF-β2 is a Prognostic Biomarker Correlated with Immune Cell Infiltration in Colorectal Cancer: A STROBE-compliant article.

Medicine (Baltimore) 2020 Nov;99(46):e23024

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's.

Transforming growth factor-beta (TGF-β2) is an important cytokine regulating immune cell function. However, whether TGF-β2 controls the invasion of colorectal cancer (CRC) by immune cells is unknown. Therefore, we evaluated the expression of TGF-β2 using multiple databases and determined the relationship between TGF-β2 expression and tumor immune infiltration defined by a set of genetic markers. The analysis demonstrated that the expression of TGF-β2 is closely related to the outcome of many cancers, and this correlation was particularly strong in CRC. In addition, the increased expression of TGF-β2 was significantly associated with the expression of various markers of specific immune cell subpopulations, and overexpression of TGF-β2 was closely related to the prognosis of colon cancer patients. Moreover, TGF-β2 was related to the prognosis and infiltration of the tumor by immune cells in CRC patients. The obtained results indicate that TGF-β2 is a critical factor regulating the recruitment of immune cells and controls their infiltration into colorectal tumors. Thus, high expression of TGF-β2 not only facilitates the prognosis in CRC patients, but also may provide a new target for the treatment of CRC.
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http://dx.doi.org/10.1097/MD.0000000000023024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668458PMC
November 2020

Geniposide inhibits proliferation and induces apoptosis of diffuse large B-cell lymphoma cells by inactivating the HCP5/miR-27b-3p/MET axis.

Int J Med Sci 2020 23;17(17):2735-2743. Epub 2020 Sep 23.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Diffuse large B-cell lymphoma (DLBCL) is commonly treated with R-CHOP, but ~30 to 50% of the patients are poorly responsive to this strategy. Geniposide, an extract from the Ellis, plays antitumor roles in human gastric cancer, hepatocellular carcinoma, and oral squamous carcinoma. However, the effects of geniposide treatment on DLBCL cells, as well as its underlying mechanism, are still unknown. Here, we found that geniposide inhibited the proliferation of OCI-LY7 and OCI-LY3 cells in a dose-dependent manner. Furthermore, geniposide increased the percentage of apoptotic cells and upregulated the levels of cleaved PARP and cleaved caspase-3 in DLBCL cells. Interestingly, geniposide treatment significantly reduced the expression of the long noncoding RNA HLA complex P5 (lncRNA HCP5) in DLBCL cells. HCP5 expression was revealed to be upregulated in DLBCL tissues and cell lines. Moreover, HCP5 knockdown resulted in proliferation inhibition and apoptosis in OCI-LY7 and OCI-LY3 cells. miR-27b-3p was predicted as a potential target of HCP5 using the lnCAR web tool. Both HCP5 silencing and geniposide treatment increased the level of miR-27b-3p in DLBCL cells. Accordingly, a luciferase reporter assay identified miR-27b-3p as a direct target of HCP5. The expression of miR-27b-3p was upregulated and inversely correlated with the HCP5 level in DLBCL tissues. HCP5 knockdown reduced MET protein expression, which was subsequently rescued by miR-27b-3p silencing in DLBCL cells. Importantly, the restoration of MET partially reversed the geniposide-induced proliferation inhibition and apoptosis of DLBCL cells. In conclusion, geniposide inhibits the proliferation and induces the apoptosis of DLBCL cells at least partially by regulating the HCP5/miR-27b-3p/MET axis, indicating a potential strategy for DLBCL treatment.
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http://dx.doi.org/10.7150/ijms.51329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645330PMC
August 2021

Comparison of pancreatic function and quality of life between patients with infected pancreatitis necrosis undergoing open necrosectomy and minimally invasive drainage: A long-term study.

Exp Ther Med 2020 Nov 10;20(5):75. Epub 2020 Sep 10.

Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China.

The present study aimed to determine whether a difference in pancreatic function and quality of life (QoL) is present between patients with infected pancreatitis necrosis (IPN) undergoing open necrosectomy (ON) and minimally invasive drainage (MID). The medical records of patients with IPN discharged from Jinling Hospital were retrospectively analyzed. Pancreatic function and QoL were compared between patients treated with ON and MID. Pancreatic endocrine and exocrine function were assessed using the oral glucose tolerance test and fecal elastase-1 (FE-1) test, respectively. The standard Short Form 36 health questionnaire was used to evaluate the QoL of patients. The analysis included 101 patients who underwent either ON (n=40, 39.6%) or MID (n=61, 60.4%). There were no significant differences in exocrine and endocrine pancreatic function between the two groups evaluated based on FE-1, fasting blood glucose, glycated hemoglobin and 2-h plasma glucose (P<0.05). The scores of the QoL questionnaire were significantly higher in patients treated with MID than in patients treated with ON, including the scores of general health perception (19.39±3.07 vs. 17.37±3.63, P=0.003), vitality (18.93±2.88 vs. 17.57±3.47, P=0.035), social role functioning (8.85±1.43 vs. 8.15±1.98, P=0.042), emotional role functioning (5.33±1.07 vs. 4.82±1.25, P=0.034), mental health (24.21±3.31 vs. 22.57±3.91, P=0.026) and the total QoL score (125.12±13.16 vs. 116.50±16.94, P=0.005). In conclusion, although the initial health of the patient may have influenced the treatment provided, patients with IPN who received MID achieved a better post-treatment QoL than those treated with ON. No significant differences between the two groups were observed regarding the endocrine and exocrine functions of the pancreas.
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http://dx.doi.org/10.3892/etm.2020.9203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500036PMC
November 2020

Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway.

Cell Death Dis 2020 09 9;11(9):730. Epub 2020 Sep 9.

Department of Hepatopancreatobiliary Surgery & Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), 310014, Hangzhou, China.

Bromodomain-containing protein 9 (BRD9) has a critical role in human squamous cell lung cancer, acute myeloid leukemia, and malignant rhabdoid tumors. However, the expression and biological role of BRD9 in hepatocellular carcinoma (HCC) is poorly understood. In this study, BRD9 expression was found to be elevated in HCC through data mining of public databases. Next, we confirmed that the expression of BRD9 was increased in HCC tissues compared with that in adjacent non-tumor tissues. The upregulated level of BRD9 was also observed in HCC cells in comparison to LO2 cells. The increased BRD9 expression was correlated with unfavorable clinicopathological features. A high level of BRD9 predicted a poorer overall survival and disease-free survival of HCC patients. Functionally, BRD9 overexpression facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of Hep3B cells. Conversely, either BRD9 depletion or pharmacological inhibition of BRD9 resulted in the reduced proliferation and invasiveness of HCCLM3 cells. In addition, the BRD9 knockdown restrained the growth and metastasis of HCCLM3 cells in vivo. Mechanistically, BRD9 positively regulated TUFT1 expression and AKT activation in HCC cells. ChIP-qPCR analysis indicated that BRD9 promoted the binding of P300 acetyltransferase to the TUFT1 promoter and epigenetically regulated TUFT1 expression by increasing H3K27Ac in the promoter. Notably, either TUFT1 knockdown or AKT inhibitor (MK2206) abrogated the promoting effects of BRD9 on the proliferation, migration, invasion, and EMT of Hep3B cells. The forced expression of TUFT1 abolished the effects of BRD9 knockdown on the growth and metastasis of HCCLM3 cells. Altogether, these data indicate that BRD9 promotes the growth and metastasis of HCC cells by activating the TUFT1/AKT pathway and may serve as a promising biomarker and therapeutic target for HCC.
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http://dx.doi.org/10.1038/s41419-020-02943-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481201PMC
September 2020

Long noncoding RNA PICSAR/miR-588/EIF6 axis regulates tumorigenesis of hepatocellular carcinoma by activating PI3K/AKT/mTOR signaling pathway.

Cancer Sci 2020 Nov 23;111(11):4118-4128. Epub 2020 Sep 23.

Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Accumulating evidence has identified long noncoding RNAs (lncRNAs) as regulators in tumor progression and development. Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-PICSAR (p38 inhibited cutaneous squamous cell carcinoma associated lincRNA) on the biological behaviors of HCC. In the present study, we found that PICSAR was upregulated in HCC tissues and cells and correlated with progression and poor prognosis in HCC patients. Gain- and loss-of-function experiments indicated that PICSAR enhanced cell proliferation, colony formation, and cell cycle progression and inhibited apoptosis of HCC cells. PICSAR could function as a competing endogenous RNA by sponging microRNA (miR)-588 in HCC cells. Mechanically, miR-588 inhibited HCC progression and alternation of miR-588 reversed the promotive effects of PICSAR on HCC cells. In addition, we confirmed that eukaryotic initiation factor 6 (EIF6) was a direct target of miR-588 in HCC and mediated the biological effects of miR-588 and PICSAR in HCC, resulting in PI3K/AKT/mTOR pathway activation. Our data identified PICSAR as a novel oncogenic lncRNA associated with malignant clinical outcomes in HCC patients. PICSAR played an oncogenic role by targeting miR-588 and subsequently promoted EIF6 expression and PI3K/AKT/mTOR activation in HCC. Our results revealed that PICSAR could be a potential prognostic biomarker and therapeutic target for HCC.
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http://dx.doi.org/10.1111/cas.14631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648049PMC
November 2020

Long noncoding RNA LINC01123 promotes the proliferation and invasion of hepatocellular carcinoma cells by modulating the miR-34a-5p/TUFT1 axis.

Int J Biol Sci 2020 5;16(13):2296-2305. Epub 2020 Jun 5.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.

Hepatocellular carcinoma (HCC), one of the main causes of cancer-related deaths globally, is characterized by rapid growth and high invasiveness. Accumulating evidence demonstrates that long noncoding RNAs (lncRNAs) play critical roles in the growth and metastasis of HCC. Recently, lncRNA LINC01123 has been found to contribute to cell proliferation and aerobic glycolysis in lung cancer. However, the function of LINC01123 in HCC, as well as the underlying mechanism of its action, remain unclear. Here, we found that the expression of LINC01123 was clearly upregulated in HCC tissues compared to nontumor tissues. Furthermore, expression of LINC01123 in HCC cells was significantly higher than in LO2 cells. Importantly, the upregulated level of LINC01123 was related to unfavorable clinical features and poor prognosis of HCC. Next, we demonstrated that LINC01123 knockdown suppressed the proliferation, migration and invasion of HCC cells . Depletion of LINC01123 inhibited HCC xenograft growth . Conversely, ectopic expression of LINC01123 facilitated HCC cell proliferation and invasion. Mechanistically, LINC01123 acted as a molecular sponge for miR-34a-5p in HCC cells. Tuftelin1 (TUFT1) was identified as the target gene of miR-34a-5p. LINC01123 positively regulated TUFT1 level by targeting of miR-34a-5p in HCC cells. Notably, TUFT1 restoration can abolish miR-34a-5p-induced inhibitory effects on HCC cell proliferation, migration and invasion. In conclusion, LINC01123 was overexpressed in HCC and accelerated cancer cell proliferation and invasion by regulating the miR-34a-5p/TUFT1 axis.
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http://dx.doi.org/10.7150/ijbs.45457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378647PMC
June 2020

Application of nomogram containing log odds of metastatic lymph node in gallbladder cancer patients.

Ann Transl Med 2020 May;8(10):655

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

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http://dx.doi.org/10.21037/atm-2020-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290604PMC
May 2020

TGFβ2 is a prognostic-related biomarker and correlated with immune infiltrates in gastric cancer.

J Cell Mol Med 2020 07 12;24(13):7151-7162. Epub 2020 Jun 12.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

TGFβ2 is an essential regulator of immune cell functionality, but the mechanisms whereby it drives immune infiltration in gastric cancer remain uncertain. The Oncomine and Tumor Immunoassay Resource (TIMER) databases were used for assessing the expression of TGFβ2, after which TIMER was used to explore the relationship between TGFβ2 and tumour immune infiltration. Finally, we assessed how TGFβ2 expression correlated with the expression of a set of marker genes associated with immune infiltration using TIMER and GEPIA. We determined TGFβ2 expression to be significantly correlated with outcome in multiple types of cancer in the Cancer Genome Atlas (TCGA), with the effect being particularly pronounced in gastric cancer. Furthermore, elevated TGFβ2 expression was found to be significantly correlated with gastric cancer N staging, and with the expression of a variety of immune markers associated with particular immune cell subsets. These results indicate that TGFΒ2 is associated with patient outcome and tumour immune cell infiltration in multiple cancer types. This suggests that TGFβ2 is a key factor which governs immune cell recruitment to gastric cancer tumours, potentially playing a vital role in governing immune cell infiltration and thus representing a valuable prognostic biomarker in gastric cancer patients.
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http://dx.doi.org/10.1111/jcmm.15164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339175PMC
July 2020

The genetic association between type 2 diabetic and hepatocellular carcinomas.

Ann Transl Med 2020 Mar;8(6):380

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: Type 2 diabetes mellitus (T2DM) and hepatocellular carcinoma (HCC) are both major health problems throughout the world. It has been reported that T2DM is an independent risk factor for HCC, although the pathophysiology is still unclear.

Methods: In order to identify differentially expressed genes (DEGs) in T2DM and HCC, gene expression datasets for T2DM (GSE15653), HCC (GSE60502) and metformin-treated cells (GSE69850) were obtained from the Gene Expression Omnibus database repository. Protein-protein interaction (PPI) networks for the DEGs were constructed and gene clusters selected for functional enrichment analysis. Ten genes with the highest degree of connectivity were selected as hub genes and prognostic analysis together with analysis of gene expression and protein distribution were performed for these genes. Lastly, we investigated associations between the hub genes and genes associated with metformin treatment in hepatocarcinoma cells.

Results: In total, 256 common DEGs, including 155 up-regulated genes and 101 down-regulated genes, were identified. Enrichment analyses showed that the genes of the major module were largely associated with the cell cycle. All of the 10 hub genes ( and ) have a strong association with lower overall survival in liver cancer patients and four genes ( and ) have reduced expression in metformin-treated samples.

Conclusions: This study identified a number of genes that may play important roles in the association of T2DM and HCC, including four genes which may be the target of metformin treatment for diabetes and HCC. The specific mechanisms involved remain to be identified.
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http://dx.doi.org/10.21037/atm.2020.02.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186634PMC
March 2020

FBW7 in hematological tumors.

Oncol Lett 2020 Mar 8;19(3):1657-1664. Epub 2020 Jan 8.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China.

F-box and WD repeat domain-containing protein 7 (FBW7), also known as FBXW7, AGO or hCDC4, is an F-box protein with seven tandem WD40 repeats. FBW7 is a key substrate recognition subunit of the Skp1-Cul1-F-box-protein E3 ubiquitin ligase. FBW7 targets for ubiquitination and destruction of numerous crucial transcription factors and protooncogenes, including cyclin E, c-Myc, c-Jun, Notch and MCL-1. FBW7 is a well-characterized tumor suppressor, and its gene is frequently mutated or deleted in various types of human cancer, including colorectal cancer, gastric cancer, ovarian cancer and different types of leukemia. Accumulating evidence indicates that the aberrant expression of FBW7 is involved in the development of hematological tumors, including T cell acute lymphoblastic leukemia, adult T cell leukemia/lymphoma, chronic lymphocytic leukemia and multiple myeloma. The present review will describe the latest findings on the role of FBW7 in hematological tumors, in order to identify a novel target for future therapies.
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http://dx.doi.org/10.3892/ol.2020.11264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039162PMC
March 2020

A new nomogram from the SEER database for predicting the prognosis of gallbladder cancer patients after surgery.

Ann Transl Med 2019 Dec;7(23):738

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: To study the prognostic significance in gallbladder cancer (GBC) patients of the four N stage methods of log odds of positive lymph nodes (LODDS), lymph node ratio (LNR), and N stage in the 7th and 8 editions of the American Joint Committee on Cancer (AJCC), and to establish a prognostic model of GBC based on LODDS.

Methods: Data of 1,321 patients with GBC who underwent surgical resection of lymph nodes from 2010 to 2014 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. We then randomly divided these data into a training set (n=925) and a validation set (n=396). C-index, Akaike information criterion (AIC), and area under the curve (AUC) were calculated to evaluate the accuracy of LODDS, LNR, and N stage in the 7 and 8 editions of the AJCC. Cox multivariate analysis was performed to determine whether LODDS was an independent prognostic factor, and a nomogram model was established. C-index was used to evaluate the accuracy of the nomogram. A receiver operating characteristic (ROC) curve was drawn and the area under the AUC was calculated to evaluate the accuracy of the nomogram in predicting patients' 1-, 3-, and 5-year overall survival (OS).

Results: Univariate analysis showed that the four methods were all correlated with OS. Through C-index, AIC and AUC, We found that LODDS had the best accuracy of the four methods. C-index and AUC analysis revealed that the nomogram based on LODDS had excellent prognostic ability. All the results were verified in the validation set.

Conclusions: LODDS is an independent prognostic factor for GBC patients, and it is the best N stage in the SEER database. This new nomogram-containing LODDS system is a great model to predict the prognosis of GBC patients.
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http://dx.doi.org/10.21037/atm.2019.11.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989982PMC
December 2019

DNA methylation-based prognostic biomarkers of acute myeloid leukemia patients.

Ann Transl Med 2019 Dec;7(23):737

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou 310014, China.

Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disease that prevents normal myeloid differentiation with its common features. Its incidence increases with age and has a poor prognosis. Studies have shown that DNA methylation and abnormal gene expression are closely related to AML.

Methods: The methylation array data and mRNA array data are from the Gene Expression Omnibus (GEO) database. Through the GEO data, we identified differential genes from tumors and normal samples. Then we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses on these differential genes. Protein-protein interaction (PPI) network construction and module analysis were performed to screen the highest-scoring modules. Next, we used SurvExpress software to analyze the genes in the highest-scoring module and selected potential prognostic genes by univariate and multivariate Cox analysis. Finally, the three genes screened by SurvExpress software were analyzed using the methylation analysis site MethSurv to explore AML associated methylation biomarkers.

Results: We found three genes that can be used as independent prognostic factors for AML. These three genes are the low expression/methylation genes ATP11A and ITGAM, and the high expression/low methylation gene ZNRF2.

Conclusions: In this study, we performed a comprehensive analysis of DNA methylation and gene expression to identify key epigenetic genes in AML.
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http://dx.doi.org/10.21037/atm.2019.11.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989983PMC
December 2019

Regulatory effect of chemerin and therapeutic efficacy of chemerin‑9 in pancreatogenic diabetes mellitus.

Mol Med Rep 2020 Mar 8;21(3):981-988. Epub 2020 Jan 8.

Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China.

Chemerin is a novel adipokine that regulates immune responses, adipocyte differentiation, and glucose metabolism. However, the role of chemerin in pancreatogenic diabetes mellitus (PDM) remains unknown. PDM is recognized as DM occurring secondary to chronic pancreatitis or pancreatic resection due to the loss of the loss of islet cell mass. The aim of the present study was to investigate the role of chemerin in PDM by collecting blooding samples from DM patients and establishing in vivo PDM model. The present study demonstrated that chemerin levels are decreased in the serum of patients with PDM and are negatively associated with the insulin resistance (IR) status. Chemerin levels also decreased during the development of PDM in C57BL/6 mice, together with increasing serum levels of interleukin‑1 and tumor necrosis factor‑α and decreasing mRNA expression levels of glucose transporter 2 (GLUT2) and pancreatic and duodenal homeobox 1 (PDX1). Treatment of PDM model mice with chemerin chemokine‑like receptor 1 (CMKLR1) agonist, chemerin‑9, elevated the serum levels of chemerin and mRNA expression levels of GLUT2 and PDX1, leading to the alleviation of glucose intolerance and IR in these animals. Together, the accumulated data indicated that chemerin may exert a protective function in PDM, perhaps by regulating perhaps by regulating GLUT2 and PDX1 expression, and that the restoration of the chemerin/CMKLR1 pathway may represent a novel therapeutic strategy for PDM.
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http://dx.doi.org/10.3892/mmr.2020.10915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002998PMC
March 2020

miR-4666-3p and miR-329 Synergistically Suppress the Stemness of Colorectal Cancer Cells via Targeting TGF-β/Smad Pathway.

Front Oncol 2019 19;9:1251. Epub 2019 Nov 19.

Key Laboratory of Tumor Microenvironment and Immune Therapy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Quiescent caner stem cells are identified as a subpopulation of colon cancer cells in dormant state and possess strong stem-cell like characteristics. Previously, we have identified this subpopulation in colorectal cancer (quiescent colon cancer stem cells, QCCSCs), and find QCCSCs are sensitive to the apoptotic effect of IFN-γ, which is attributed to their high IFN-γR expression levels. Microarray and bioinformatic analysis indicate miR-4666-3p is low expressed in QCCSCs and target IFN-γR1/2, which is proved by luciferase assay and western-blot. Furthermore, we find miR-4666-3p could also target TGF-βR1 to block the activation of TGF-β1/Smad pathway, therefore function as a tumor suppressor gene to inhibit the stemness of colon cancer cells. Besides, compared with QCCSCs, we find the TGF-β1 expression also decreased with the weakening of stemness properties. In terms of mechanism, our result reveal TGF-β1 is the target gene of miR-329, which is also high expressed in non-QCCSCs. Thereafter, we perform gain- and loss- function experiments to confirm the synergistic effect between miR-4666-3p and miR-329 in blocking the activation of TGF-β/Smad pathway. Finally, we evaluate the expression of both miR-4666-3p and miR-329 in 73 tumor specimens and paired normal tissue, and find both two miRNAs are related to unfavorable prognosis and advanced tumor stage in colorectal cancer. Our study revealed a novel epigenetic regulation mechanism in colon cancer stem cells, which could be exploited as a novel therapeutic strategy for cancer treatment.
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http://dx.doi.org/10.3389/fonc.2019.01251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880832PMC
November 2019

Hypoxia‑inducible factors in hepatocellular carcinoma (Review).

Oncol Rep 2020 Jan 1;43(1):3-15. Epub 2019 Nov 1.

The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang 310014, P.R. China.

Maintenance of an appropriate oxygen concentration is essential for the function of the liver. However, in many pathological conditions, and particularly in the tumor microenvironment, cells and tissues are frequently in a hypoxic state. In the presence of hypoxia, the cells adapt to the low oxygen levels through the hypoxia‑inducible factor (HIF) pathway. Overgrowth of tumor cells restricts the diffusion of oxygen in tumors, leading to insufficient blood supply and the creation of a hypoxic microenvironment, and, as a consequence, activation of the expression of HIFs. HIFs possess a wide range of target genes, which function to control a variety of signaling pathways; thus, HIFs modulate cellular metabolism, immune escape, angiogenesis, metastasis, extracellular matrix remodeling, cancer stem cells and other properties of the tumor. Given their crucial role in the occurrence and development of tumors, HIFs are expected to become new targets of precise treatment of hepatocellular carcinoma.
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http://dx.doi.org/10.3892/or.2019.7397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908932PMC
January 2020

CD68- and CD163-positive tumor infiltrating macrophages in non-metastatic breast cancer: a retrospective study and meta-analysis.

J Cancer 2019 23;10(19):4463-4472. Epub 2019 Jul 23.

Department of Breast Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310003, China.

Studies have indicated the significance of tumor associated macrophages (TAMs) in breast cancer; however, inconsistent results still exist. We retrospectively reviewed the macrophage distribution in 1579 breast cancer specimens with anti-CD68 or anti-CD163 immunohistochemical staining, and further analyzed the overall survival data. Furthermore, we performed a retrospective study and systematic review of the published studies on CD68- and CD163-positive macrophages in non-metastatic breast cancer. 13 studies with 5116 patients were included in this meta-analysis. Our own data revealed a high density of both CD68- and CD163-positive TAMs that was significantly related to lymph node metastasis (CD68, = 0.003; CD163, < 0.001); high Ki67 (CD68, = 0.026; CD163, < 0.001), poor histological grade (CD68, < 0.001; CD163, < 0.001) and hormonal receptor negativity (CD68, < 0.001; CD163, < 0.001); only CD163-positive TAMs were associated with poor overall survival ( = 0.003). Nonetheless, the meta-analysis only found that CD68- and CD163-positive TAMs were associated with high Ki67 [CD68, Relative risk (RR): 1.18, 95% confidence interval (CI): 1.09-1.28; CD163, RR: 1.75, 95% CI: 1.39-2.20], advanced histological grade (CD68, RR: 1.72, 95% CI: 1.46-2.03; CD163, RR: 1.99, 95% CI: 1.35-2.94) and low hormonal receptor levels (CD68, RR: 0.75, 95% CI: 0.69-0.82; CD163, RR: 0.82, 95% CI: 0.74-0.90), but not lymph node metastasis and HER2 expression. This meta-analysis further supports the clinical significance of TAMs in breast cancer, and both CD68- and CD163-positive TAMs could be prognostic markers in non-metastatic breast cancer.
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http://dx.doi.org/10.7150/jca.33914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746141PMC
July 2019

Long non-coding RNA SNHG16 promotes proliferation and inhibits apoptosis of diffuse large B-cell lymphoma cells by targeting miR-497-5p/PIM1 axis.

J Cell Mol Med 2019 11 4;23(11):7395-7405. Epub 2019 Sep 4.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China.

The aberrant expression and dysfunction of long non-coding RNAs (lncRNAs) have been identified as critical factors governing the initiation and progression of different human cancers, including diffuse large B-cell lymphoma (DLBCL). LncRNA small nucleolar RNA host gene 16 (SNHG16) has been recognized as a tumour-promoting factor in various types of cancer. However, the biological role of SNHG16 and its underlying mechanism are still unknown in DLBCL. Here we disclosed that SNHG16 was overexpressed in DLBCL tissues and the derived cell lines. SNHG16 knockdown significantly suppressed cell proliferation and cell cycle progression, and it induced apoptosis of DLBCL cells in vitro. Furthermore, silencing of SNHG16 markedly repressed in vivo growth of OCI-LY7 cells. Mechanistically, SNHG16 directly interacted with miR-497-5p by acting as a competing endogenous RNA (ceRNA) and inversely regulated the abundance of miR-497-5p in DLBCL cells. Moreover, the proto-oncogene proviral integration site for Moloney murine leukaemia virus 1 (PIM1) was identified as a novel direct target of miR-497-5p. SNHG16 overexpression rescued miR-497-5p-induced down-regulation of PIM1 in DLBCL cells. Importantly, restoration of PIM1 expression reversed SNHG16 knockdown-induced inhibition of proliferation, G0/G1 phase arrest and apoptosis of OCI-LY7 cells. Our study suggests that the SNHG16/miR-497-5p/PIM1 axis may provide promising therapeutic targets for DLBCL progression.
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http://dx.doi.org/10.1111/jcmm.14601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815839PMC
November 2019

HBV Integration-mediated Cell Apoptosis in HepG2.2.15.

J Cancer 2019 10;10(17):4142-4150. Epub 2019 Jul 10.

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of cancer deaths in the word. Hepatitis B virus (HBV) infection plays an important role in the development of HCC. However, the mechanisms by which HBV integration affects host cells remain poorly understood. HepG2.2.15 cell line is derived from HCC cell line HepG2 with stable transfection HBV expression. In this study, HepG2.2.15 cells showed decreased proliferation, G1 cell cycle arrest and increased apoptosis, when compared to HepG2 cells. HBV capture sequencing was conducted in both genome and transcriptome level, followed by RNA expression sequencing in HepG2.2.15. Here, were found to be targets for HBV integration in both genome and transcriptome level, accompanied by alteration in their expression when compared to HepG2. Among these genes, was the only one gene with HBV integration into its exon, meanwhile expression level was also downregulated in HepG2.2.15 as compared to HepG2. Furthermore, knockdown resulted in increased apoptosis through upregulation of the Bax/Bcl2 ratio in HepG2 cells. Our results suggest that HBV integration of was involved in cell apoptosis.
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http://dx.doi.org/10.7150/jca.30493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692610PMC
July 2019

MicroRNA-301b-3p contributes to tumour growth of human hepatocellular carcinoma by repressing vestigial like family member 4.

J Cell Mol Med 2019 08 17;23(8):5037-5047. Epub 2019 Jun 17.

Key Laboratory of Tumour Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province, China.

MicroRNAs (miRNAs) are key regulators in the tumour growth and metastasis of human hepatocellular carcinoma (HCC). Increasing evidence suggests that miR-301b-3p functions as a driver in various types of human cancer. However, the expression pattern of miR-301b-3p and its functional role as well as underlying molecular mechanism in HCC remain poorly known. Our study found that miR-301b-3p expression was significantly up-regulated in HCC tissues compared to adjacent non-tumour tissues. Clinical association analysis revealed that the high level of miR-301b-3p closely correlated with large tumour size and advanced tumour-node-metastasis stages. Importantly, the high miR-301b-3p level predicted a prominent poorer overall survival of HCC patients. Knockdown of miR-301b-3p suppressed cell proliferation, led to cell cycle arrest at G2/M phase and induced apoptosis of Huh7 and Hep3B cells. Furthermore, miR-301b-3p knockdown suppressed tumour growth of HCC in mice. Mechanistically, miR-301b-3p directly bond to 3'UTR of vestigial like family member 4 (VGLL4) and negatively regulated its expression. The expression of VGLL4 mRNA was down-regulated and inversely correlated with miR-301b-3p level in HCC tissues. Notably, VGLL4 knockdown markedly repressed cell proliferation, resulted in G2/M phase arrest and promoted apoptosis of HCC cells. Accordingly, VGLL4 silencing rescued miR-301b-3p knockdown attenuated HCC cell proliferation, cell cycle progression and apoptosis resistance. Collectively, our results suggest that miR-301b-3p is highly expressed in HCC. miR-301b-3p facilitates cell proliferation, promotes cell cycle progression and inhibits apoptosis of HCC cells by repressing VGLL4.
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http://dx.doi.org/10.1111/jcmm.14361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653225PMC
August 2019
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