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Objective Tumor cells could acquire drug resistance through cell autophagy. This study aimed to explore the role of SNHG16 in sorafenib‐resistant HCC cells and its mechanism with miR‐23b‐3p. Methods The sorafenib‐resistant Hep3B cell model was established. The SNHG16 and miR‐23b‐3p gene expressions were determined in normal HCC and sorafenib‐resistant HCC tissues. Detection of the expression of SNHG16 and miR‐23b‐3p and its respective correlation with survival rate were performed. Target genes to SNHG16 and miR‐23b‐3p were predicted, and verified by dual‐fluorescent reporter assay. The effects of SNHG16 and miR‐23b‐3p on SNHG16, miR‐23b‐3p, EGR1 expression, viability, apoptosis as well as LC3II/LC3 expression in Hep3B and Hep3B/So cells were detected by qRT‐PCR, CCK‐8, flow cytometry, and western blot. In in vivo studies, the NOD/SCID mice model was established to explore the effects of Hep3B and Hep3B/So cells with inhibited SNHG16 or miR‐23b‐3p on tumor size, EGR1 expression, and autophagy. Results High SNHG16 expression in HCC‐resistant tissues and low miR‐23b‐3p expression in all HCC tissues were detected, and the two were negatively correlated. Low SNHG16 and high miR‐23b‐3p were related to a high survival rate of HCC patients. Moreover, SNHG16 overexpression promoted Hep3B/So cell viability and autophagy, suppressed apoptosis by inhibiting miR‐23b‐3p expression through up‐regulating EGR1, however, the effect of si‐SNHG16 was opposite. In in vivo studies, miR‐23b‐3p inhibitor suppressed the high sorafenib sensitivity in Hep3B/So cells caused by SNHG16 silencing through promoting viability, autophagy, and suppressing apoptosis. Conclusion SNHG16 promotes Hep3B/So cell viability, autophagy, and inhibits apoptosis to maintain its resistance to sorafenib through regulating the expression of miR‐23b‐3p via sponging EGR1., This study demonstrated the promoter role of SNHG16 played in regulating autophagy in Hep3B cells with sorafenib resistance, which further contribute to a stronger sorafenib resistance in Hep3B cells. Moreover, the above process implemented through regulating the expression of miR‐23b‐3p via sponging EGR1.

Hepatocellular carcinoma (HCC) is a prevalent liver malignancy that can be developed from nonalcoholic fatty liver disease (NAFLD). Numerous pathophysiological alterations, including insulin resistance, specific cytokine release, oxidative stress, and mitochondrial damage, are involved in the transition of NAFLD to cirrhosis and HCC. MicroRNAs, as post-transcriptional modulators, play a critical role in the pathogenesis of NAFLD-related HCC by regulating lipid metabolism, glucose homeostasis, cell proliferation, apoptosis, migration, and differentiation. This review summarizes the current progress of microRNAs in the risk and prognosis of NAFLD-related HCC. Anat Rec, 302:193-200, 2019. © 2018 Wiley Periodicals, Inc.

// Cheng Zhang 1 , Jinyun Li 2 , Tao Huang 2 , Shiwei Duan 2 , Dongjun Dai 2 , Danjie Jiang 2 , Xinbing Sui 3 , Da Li 3 , Yidan Chen 1 , Fei Ding 1 , Changxin Huang 1 , Gongying Chen 1 , Kaifeng Wang 1 1 Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China 2 Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, China 3 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China Correspondence to: Kaifeng Wang, email: wangkf2000@163.com Gongying Chen, email: chengongying@hotmail.com Keywords: meta-analysis, DNA methylation, biomarker, hepatocellular carcinoma Received: May 03, 2016 Accepted: November 01, 2016 Published: November 08, 2016 ABSTRACT DNA methylation is an epigenetic mechanism in the pathogenesis of hepatocellular carcinoma (HCC). Here, we conducted a systematic meta-analysis to evaluate the contribution of DNA methylation to the risk of HCC. A total of 2109 publications were initially retrieved from PubMed, Web of Science, Cochrane Library, Embase, CNKI and Wanfang literature database. After a four-step filtration, we harvested 144 case-control articles in the meta-analysis. Our results revealed that 24 genes (carcinoma tissues vs adjacent tissues), 17 genes (carcinoma tissues vs normal tissues) and six genes (carcinoma serums vs normal serums) were significantly hypermethylated in HCC. Subgroup meta-analysis by geographical populations showed that six genes (carcinoma tissues vs adjacent tissues) and four genes (carcinoma tissues vs normal tissues) were significantly hypermethylated in HCC. Our meta-analysis identified the correlations between a number of aberrant methylated genes ( p16 , RASSF1A , GSTP1 , p14 , CDH1 , APC , RUNX3 , SOCS1 , p15 , MGMT , SFRP1 , WIF1 , PRDM2 , DAPK1 , RARβ , hMLH1 , p73 , DLC1 , p53 , SPINT2 , OPCML and WT1 ) and HCC. Aberrant DNA methylation might become useful biomarkers for the prediction and diagnosis of HCC.

Objective. The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods. We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3–76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results. For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions. The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype–phenotype correlations in hyperbilirubinemia patients.

The search for novel anti-hepatocellular carcinoma (HCC) agents is important. Mammalian target of rapamycin (mTOR) hyper-activation plays a pivotal role in promoting HCC tumorigenesis and chemoresistance. The current preclinical study evaluated the potential anti-HCC activity by a potent mTOR kinase inhibitor, WAY-600. We showed that WAY-600 inhibited survival and proliferation of HCC cell lines (HepG2 and Huh7) and primary human HCC cells. Caspase-dependent apoptosis was activated by WAY-600 in above HCC cells. Reversely, caspase inhibitors largely attenuated WAY-600's lethality against HCC cells. At the signaling level, WAY-600 blocked mTOR complex 1/2 (mTORC1/2) assemble and activation, yet activated MEK-ERK pathway in HCC cells. MEK-ERK inhibitors, PD-98059 and MEK-162, or MEK1/2 shRNA significantly potentiated WAY-600's cytotoxicity in HCC cells. Further studies showed that WAY-600 intraperitoneal (i.p.) administration in nude mice inhibited p-AKT Ser-473 and displayed significant anti-cancer activity against HepG2 xenografts. Remarkably, co-administration of MEK-162 further potentiated WAY-600's anti-HCC activity in vivo. These preclinical results demonstrate the potent anti-HCC activity by WAY-600, either alone or with MEK-ERK inhibitors.

Chinese medicines are emerging as an attractive new generation of anticancer drugs. Here, we explored the impact of salvianolic acid B (Sal B), the major water-soluble compounds of Danshen, on apoptosis and autophagy of human hepatocellular carcinoma cells (HCC). We also investigated the related molecular mechanisms. We found that Sal B exhibits potent ability to inhibit HCC cells viability in a concentration-dependent manner, and to induce apoptosis via the mitochondrial apoptosis pathway. Additionally, Sal B could also induce autophagy. Furthermore, pretreatment with the autophagy inhibitor chloroquine or 3-methyladenine showed the potential in attenuating the apoptosis rate induced by Sal B. Mechanistically, Sal B treatment inhibited the AKT/mTOR signaling cascade in vitro. Overexpression of AKT abolished the effects of Sal B on HCC cells, suggesting a critical role of the AKT/mTOR signaling pathway in Sal B-induced biological effects. Our results indicated that the mitochondrial pathway was involved in Sal B-induced apoptosis of HCC cells. Moreover, the AKT/mTOR signaling pathway was involved in Sal B-induced autophagy, which promoted apoptosis. This study may provide a promising strategy for using Sal B as a chemotherapeutic agent for patients with HCC.