Correction: Lai et al. MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling. Cancers 2021, 13, 940

MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

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Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model

Biochemical Pharmacology ◽

10.1016/j.bcp.2021.114497 ◽

2021 ◽

pp. 114497

Author(s):

Yasmeen M Attia ◽

Rasha A Tawfiq ◽

Abdullah A Gibriel ◽

Aya A Ali ◽

Dina H Kassem ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Animal Model ◽

Stat3 Signaling ◽

Signaling Axis

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CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01769-7 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Zhongwei Zhao ◽

Jingjing Song ◽

Bufu Tang ◽

Shiji Fang ◽

Dengke Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Migration ◽

Real Time ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Signaling Axis

Abstract Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

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3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Biology ◽

10.3390/biology11010029 ◽

2021 ◽

Vol 11 (1) ◽

pp. 29

Author(s):

Chakrabhavi Dhananjaya Mohan ◽

Min Hee Yang ◽

Shobith Rangappa ◽

Arunachalam Chinnathambi ◽

Sulaiman Ali Alharbi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Tyrosine Kinases ◽

Present Report ◽

Migration And Invasion ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Substantial Toxicity ◽

Transcription 3 ◽

Constitutive Phosphorylation

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

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Physagulide Q suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells by regulating the ROS-JAK2/Src-STAT3 signaling pathway

RSC Advances ◽

10.1039/c6ra25032g ◽

2017 ◽

Vol 7 (21) ◽

pp. 12793-12804 ◽

Cited By ~ 4

Author(s):

Yan-Wei Yang ◽

Lei Yang ◽

Chao Zhang ◽

Cai-Yun Gao ◽

Ting Ma ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Natural Compound ◽

Carcinoma Cells ◽

Human Hepatocellular Carcinoma ◽

Hepatocellular Carcinoma Cells ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Physalis Angulata ◽

Human Hepatocellular Carcinoma Cells

Physagulide Q (PQ), a new natural compound, was isolated from Physalis angulata L. in our laboratory.

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IL-37b suppresses epithelial mesenchymal transition in hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling

Hepatobiliary & Pancreatic Diseases International ◽

10.1016/j.hbpd.2018.08.009 ◽

2018 ◽

Vol 17 (5) ◽

pp. 408-415 ◽

Cited By ~ 2

Author(s):

Xing-Yu Pu ◽

Dao-Feng Zheng ◽

Ai Shen ◽

Hai-Tao Gu ◽

Xu-Fu Wei ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Stat3 Signaling

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Crocetin Imparts Antiproliferative Activity via Inhibiting STAT3 Signaling in Hepatocellular Carcinoma

IUBMB Life ◽

10.1002/iub.2555 ◽

2021 ◽

Author(s):

Chakrabhavi Dhananjaya Mohan ◽

Chulwon Kim ◽

Kodappully Sivaraman Siveen ◽

Kanjoormana Aryan Manu ◽

Shobith Rangappa ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Antiproliferative Activity ◽

Stat3 Signaling

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Yu Ping Feng San Exert Anti-Angiogenesis Effects through the Inhibition of TSLP-STAT3 Signaling Pathways in Hepatocellular Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1947156 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Qin Yuan ◽

Fei Yao ◽

Liang Zhou ◽

Guoqiang Liang ◽

Xiudao Song ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Performance ◽

Inhibitory Effect ◽

Tube Formation ◽

Significant Inhibition ◽

Related Factor ◽

Related Factors ◽

Chemotherapy Drugs ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

Background. Clinically, Yu ping feng san (YPFS) has been extensively used as a medication for treating immune deficiency, and YPFS is combined with chemotherapy drugs to treat cancer, including hepatocellular carcinoma (HCC), lung cancer, and pancreatic cancer. Previous research has shown that YPFS has a therapeutic effect on HCC by improving the immunosuppressive state of the liver cancer microenvironment. The present study aimed to investigate the effect of YPFS on angiogenesis of HCC. Methods. High-performance liquid chromatography (HPLC) was used to certify the composition of YPFS. An orthotopic transplanted model of murine HCC was entrenched. Immunohistochemistry was used to observe the changes of the microvessel density (MVD). The MTT assay was used to detect the cell viability. ELISA was performed to analyze the expression of related factors. Western blot was used to analyze the protein expression. Tube formation assay was used to analyze the anti-angiogenic efficiency. Results. YPFS significantly reduced the tumor volume and weight, thus exerted the growth inhibitory effect. The level of MVD and VEGF was obviously decreased in YPFS-treated HCC-bearing mice, and the YPFS treatment also reduced the VEGF level in Hepa1-6 cells. Further study revealed that the expression of TSLP/TSLPR and p-STAT3/STAT3 was decreased by YPFS. The level of MVD and VEGF and the expression of TSLP/TSLPR and p-STAT3/STAT3 in tumor tissue and Hepa1-6 cells were suppressed by incubation with the anti-TSLP antibody, whereas treatment with the anti-TSLP antibody in YPFS-treated cells did not cause further significant inhibition compared with the cells treated only with YPFS. More importantly, YPFS inhibited proliferation, expression of p-STAT3/STAT3, and tube formation of HUVECs induced by TSLP. Conclusions. These results indicated that YPFS attenuated the activation of the TSLP-STAT3 signaling pathway by inhibiting the immune-related factor-TSLP, thereby inhibiting the formation of hepatic microvessels and exerting an anti-HCC effect.

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