miR-186 Represses Proliferation, Migration, Invasion, and EMT of Hepatocellular Carcinoma via Directly Targeting CDK6

The present study aimed to investigate the effect of miR-186 on proliferation, migration, invasion, and epithelialmesenchymal transition (EMT) of hepatocellular carcinoma (HCC). In this work, miR-186 was downregulated in HCC tissues and cells, and low miR-186 level helped predict the occurrence of vascular invasion and poor prognosis in patients with HCC. miR-186 overexpression inhibited cell proliferation and tumor growth in nude mice, repressed migration and invasion abilities, and enhanced apoptosis in HCC cells. miR-186 also retarded progression of EMT. miR-186 directly bound to the 3-untranslated regions of cyclin-dependent kinase 6 (CDK6) to inhibit its expression. Overexpression of CDK6 markedly reversed inhibitory effects of miR-186 on proliferation, apoptosis, migration, and invasion of HCC cells. Conversely, inhibition of CDK6 exerted synergic effect on the biological functions of miR-186. In conclusion, miR-186 represses proliferation, migration, invasion, and EMT, and induces apoptosis through targeting CDK6 in HCC, which may provide a new therapeutic target for HCC.

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Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma

Disease Markers ◽

10.1155/2019/8964015 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Jie Zhang ◽

Qianqian Song ◽

Jinxia Liu ◽

Lina Lu ◽

Yuqing Xu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Disease Free Survival ◽

Normal Liver ◽

Regulatory Subunit ◽

Mrna Levels ◽

Cyclin Dependent Kinase ◽

Normal Tissues ◽

Hcc Cells

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P=0.019), poor differentiation (P=0.02), portal vein invasion (P<0.001), TNM stage (P=0.019), tumor metastasis (P=0.008), and recurrence (P=0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR=2.088, P=0.014) and disease-free survival (HR=2.511, P=0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P=0.0003), chemoresistance, migration (P=0.0047), and invasion (P=0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of HCC.

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LncRNA PITPNA-AS1 as a Potential Diagnostic Marker and Therapeutic Target Promotes Hepatocellular Carcinoma Progression via Modulating miR-448/ROCK1 Axis

Frontiers in Medicine ◽

10.3389/fmed.2021.668787 ◽

2021 ◽

Vol 8 ◽

Author(s):

Qing-fang Wang ◽

Qing-lin Wang ◽

Ming-bo Cao

Keyword(s):

Hepatocellular Carcinoma ◽

Antisense Rna ◽

Diagnostic Marker ◽

Luciferase Assay ◽

Migration And Invasion ◽

Biological Functions ◽

Non Coding Rnas ◽

Hcc Cells

Background: Long non-coding RNAs are critical to hepatocellular carcinoma (HCC) developments. LncRNA PITPNA antisense RNA 1 (PITPNA-AS1) is a new regulator in several tumors. However, the mechanism by which PITPNA-AS1 mediates the tumorigenesis of HCC remains unclear.Methods: RT-qPCR was used to detect the level of PITPNA-AS1 in HCC specimens and cells. The biological functions of PITPNA-AS1 were explored by several functional experiments in vivo and in vitro. The binding relationship among PITPNA-AS1, miR-448 and ROCK1 were studied by Luciferase assay and pull-down assays.Results: We found that PITPNA-AS1 expressions were distinctly upregulated in both HCC specimens and cell lines. High PITPNA-AS1 levels were an unfavorable biomarker for patients with HCC. Functionally, knockdown of PITPNA-AS1 suppressed the proliferation, migration and invasion of HCC cells. Mechanistically, PITPNA-AS1 functioned as competing endogenous RNA to increase ROCK1 expressions via sponging miR-448.Conclusion: The newly identified PITPNA-AS/miR-448/ROCK1 axis promoted the oncogenicity of HCC cells. This novel axis is likely to be a promising HCC therapeutic aim.

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Kinesin family member 2C promotes hepatocellular carcinoma growth and metastasis via activating MEK/ERK pathway

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab154 ◽

2021 ◽

Author(s):

Qian Ding ◽

Caihua Jiang ◽

Yajing Zhou ◽

Jianping Duan ◽

Jianming Lai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Family Member ◽

Poor Prognosis ◽

Migration And Invasion ◽

Erk Pathway ◽

High Level ◽

The Impact ◽

Kinesin Family ◽

Hcc Cells

ABSTRACT The current work was intended to explore the function and mechanism of Kinesin family member 2C (KIF2C) in hepatocellular carcinoma (HCC). In this study, KIF2C expression was at a high level in HCC and indicated poor prognosis. Silencing KIF2C significantly suppressed the proliferation, migration and invasion in HCC cells. Furthermore, silencing KIF2C markedly decreased the expression of Snail, Vimentin, p-MEK and p-ERK, but increased E-cadherin expression in HCC cells. Moreover, we also found that MEK/ERK inhibitor U0126 could enhance the impact on cell proliferation, migration and invasion induced by silencing KIF2C in HCC. On the contrary, MEK/ERK activator PAF could weaken the impact induced by silencing KIF2C in HCC. Thus, our findings indicate that KIF2C can promote the proliferation, migration and invasion by activating MEK/ERK pathway in HCC.

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miR-96 targets SOX6 and promotes proliferation, migration, and invasion of hepatocellular carcinoma

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0183 ◽

2018 ◽

Vol 96 (3) ◽

pp. 365-371 ◽

Cited By ~ 10

Author(s):

Zhengwei Li ◽

Ying Wang

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cell Lines ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Biological Functions ◽

Promote Cell Proliferation ◽

Protein Expressions ◽

Reporter Assays ◽

Hcc Cells

Recent research suggested that microRNA 96 (miR-96) might function as an oncogene in several types of cancers. Therefore, the purpose of this study was to probe into the mechanism of miR-96 in hepatocellular carcinoma (HCC) cells. HCC tissues and non-tumorous tissues, HCC cell lines, and healthy cell lines were all involved in this study. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect miR-96 and SOX6 mRNA and protein expressions. The direct regulation of miR96 on SOX6 was confirmed by luciferase reporter assays. Cell proliferation and growth were determined by MTT (3-(4,5-dimethyl–2-thiazolyl)–2,5-diphenyl–2-H-tetrazolium bromide) assay and colony formation assay. Wound healing and transwell assay were employed for migration and invasion analyses. Finally, SPSS 21.0 and GraphPad 7.0 were applied for statistical analyses. In HCC tissues, miR-96 was highly expressed while SOX6 was lowly expressed. The overexpression of miR-96 reversely inhibited the expression of SOX6, contributing to the promotion of the biological functions of HCC cells. miR-96 could promote cell proliferation, migration, and invasion in HCC by targeting SOX6.

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The long noncoding RNA lncPARP1 contributes to progression of hepatocellular carcinoma through up-regulation of PARP1

Bioscience Reports ◽

10.1042/bsr20180703 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 9

Author(s):

Heqiang Qi ◽

Yuyan Lu ◽

Jie Lv ◽

Huita Wu ◽

Jing Lu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Noncoding Rna ◽

Poor Prognosis ◽

Human Cancer ◽

Noncoding Rnas ◽

Migration And Invasion ◽

Loss Of Function ◽

Mechanistic Investigation ◽

Induced Apoptosis ◽

Hcc Cells

Hepatocellular carcinoma (HCC) accounts for a large proportion of cancer-associated mortality worldwide. The functional impact of long noncoding RNAs (lncRNAs) in human cancer is not fully understood. Here, we identified a novel oncogenic lncRNA termed as lncPARP1, which was significantly up-regulated in HCC. Increase in lncPARP1 expression was associated with age, α-fetoprotein (AFP) levels, tumor size, recurrence, and poor prognosis of HCC patients. Loss-of-function approaches showed that knockdown of lncPARP1 inhibited proliferation, migration, and invasion, while induced apoptosis in HCC cells. Moreover, mechanistic investigation demonstrated that PARP1 was an underlying target of lncPARP1 in HCC. In summary, we provide the first evidence that lncPARP1 exerts an oncogene to promote HCC development and progression, at least in part, by affecting poly (ADP-ribose) (PAR) polymerase 1 (PARP1) expression.

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Upregulation of miR-1266-5p serves as a prognostic biomarker of hepatocellular carcinoma and facilitates tumor cell proliferation, migration and invasion

Acta Biochimica Polonica ◽

10.18388/abp.2020_5569 ◽

2021 ◽

Author(s):

Yan Su ◽

Ruizhu Xie ◽

Qinyan Xu

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Poor Prognosis ◽

Prognostic Value ◽

Tnm Stage ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Elevated Expression ◽

Hcc Cells

Objective: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. This study aimed to analyze the prognostic value of microRNA-1266-5p (miR-1266-5p) in HCC patients and investigate its biological function in HCC progression. Methods: The expression of miR-1266-5p in tissues and cells was measured by quantitative real-time PCR (qRT-PCR). Cell counting kit-8 (CCK-8) assay was used to detect HCC cell proliferation. Transwell assay was performed to evaluate the migration and invasion of HCC cells. Kaplan-Meier methods and Cox regression analysis were used to assess the prognostic value of miR-1266-5p in HCC patients. The relationship between miR-1266-5p and DAB2IP was evaluated by luciferase reporter assay. Results: Relative expression of miR-1266-5p in tumor tissues, tissues from patients with advanced TNM stage (III–IV) and HCC cells was increased compared with that in corresponding control group. MiR-1266-5p expression was significantly associated with tumor size and TNM stage in HCC patients. Elevated expression of miR-1266-5p was associated with poor prognosis of HCC patients and served as an independent prognostic factor for HCC patients. Overexpression of miR-1266-5p significantly promoted, while miR-1266-5p knockdown significantly inhibited the proliferation, migration and invasion of HCC cells. DAB2IP could directly bind to the miR-1266-5p. Conclusion: Our findings indicated that elevated expression of miR-1266-5p can predict the poor prognosis of HCC patients, and promotes the proliferation, migration and invasion of HCC cells. Therefore, we predict that miR-1266-5p may be a novel biomarker and therapeutic target for the treatment of HCC.

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CircRNA hsa_circRNA_104348 promotes hepatocellular carcinoma progression through modulating miR-187-3p/RTKN2 axis and activating Wnt/β-catenin pathway

Cell Death and Disease ◽

10.1038/s41419-020-03276-1 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Guanqun Huang ◽

Min Liang ◽

Haiyan Liu ◽

Jianhong Huang ◽

Peiqing Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Expression Patterns ◽

Circular Rna ◽

Migration And Invasion ◽

Circular Rnas ◽

Biological Functions ◽

Competing Endogenous Rna ◽

Direct Target

AbstractCircular RNAs (circRNAs) have confirmed to participate in diverse biological functions in cancer. However, the expression patterns of circRNAs on hepatocellular carcinoma (HCC) remains unclear. In the present study, we clarified that hsa_circRNA_104348 was dramatically upregulated in HCC tissues and cells. Patients with HCC displaying high hsa_circRNA_104348 level possessed poor prognosis. Has_circ_104348 facilitated proliferation, migration, and invasion, meanwhile suppressed apoptosis of HCC cell. Furthermore, hsa_circRNA_104348 directly targeted miR-187–3p, could regulate miR-187-3p to affect proliferation, migration, invasion, and apoptosis of HCC cells, and may have effect on Wnt/β-catenin signaling pathway. Moreover, RTKN2 could be a direct target of miR-187-3p. In addition, knockdown of hsa_circRNA_104348 attenuated HCC tumorigenesis and lung metastasis in vivo. Taken together, these findings indicated that circular RNA hsa_circRNA_104348 might function as a competing endogenous RNA (ceRNA) to promotes HCC progression by targeting miR-187–3p/RTKN2 axis and activating Wnt/β-catenin pathway.

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SEPHS1 promotes SMAD2/3/4 expression and hepatocellular carcinoma cells invasion

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00212-7 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Shu Yang ◽

Hongying Zhang ◽

Hua Yang ◽

Jin Zhang ◽

Jiao Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Migration And Invasion ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Smad Signaling ◽

Positive Regulator ◽

Smad Proteins ◽

Hcc Cells ◽

Liver Tissues

Abstract Background Hepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive. The secreted cytokine transforming growth factor-β (TGF-β) promotes cancer metastasis by multiple mechanisms such as epithelial-mesenchymal transition and immune evasion. The canonical TGF-β signaling is largely mediated by smooth muscle actin/mothers against decapentaplegic (SMAD) proteins. The current study aims to explore the regulation of TGF-β/SMAD signaling by selenophosphate synthetase 1 (SEPHS1). Methods Immunohistochemistry was used to detect the expression of SEPHS1 in HCC and adjacent liver tissues. Western blotting and quantitative reverse-transcription PCR were used to detect the protein and mRNA levels in HCC cell lines. Cell migration and invasion were determined by transwell assay. Bioinformatic analysis was conducted to determine SEPHS1 expression in HCC and its correlation with the survival of HCC patients. Results Here we report that SEPHS1 is a positive regulator of SMAD proteins. SEPHS1 expression is up-regulated in HCC compared with adjacent liver tissues. SEPHS1 knockdown leads to decreased expression of SMAD2/3/4 and mesenchymal markers including snail, slug and N-cadherin in HCC cells. Furthermore, SEPHS1 knockdown results in a decrease in HCC cells migration and invasion, and suppresses the stimulation of HCC cells migration and invasion by TGF-β. Overexpression of SEPHS1 in HCC cells promotes cell invasion, which can be abrogated by SMAD3 knockdown. Lastly, higher expression of SEPHS1 is correlated with poor prognosis in HCC patients, as manifested by decreased overall survival and disease-free survival. Conclusions SEPHS1 is a positive regulator of TGF-β/SMAD signaling that is up-regulated in HCC. Increased SEPHS1 expression may indicate poor prognosis for patients with HCC.

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Apoptotic Effects of Xanthium strumarium via PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2176701 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Juyoung Kim ◽

Kyung Hee Jung ◽

Hyung Won Ryu ◽

Doo-Young Kim ◽

Sei-Ryang Oh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Growth ◽

Caspase 3 ◽

Mtor Pathway ◽

Terminal Deoxynucleotidyl Transferase ◽

Mechanistic Study ◽

Migration And Invasion ◽

Xanthium Strumarium ◽

Apoptotic Effects ◽

Hcc Cells

Xanthium strumarium (XS) has been traditionally used as a medicinal herb for treating inflammatory diseases, such as appendicitis, chronic bronchitis, rheumatism, and rhinitis. In this study, we yielded ethanol extracts from XS and investigated whether they could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. The XS-5 and XS-6 extracts dose-dependently inhibited the growth and proliferation in HCC cell lines. The apoptotic effects of them were observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling- (TUNEL-) positive apoptotic cells. They also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, they inhibited the invasion and migration of HCC cells. In an ex vivo model, the extracts significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of the cleaved caspase-3. A mechanistic study revealed that they effectively suppressed PI3K/AKT/mTOR signaling pathways in HCC cells. Taken together, our findings demonstrate that they could efficiently not only induce apoptosis but also inhibit cell growth, migration, and invasion of human HCC cells by blocking the PI3K/AKT/mTOR pathway. We suggest XS-5 and XS-6 as novel natural anti-HCC agents.

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A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

Journal of Personalized Medicine ◽

10.3390/jpm11050332 ◽

2021 ◽

Vol 11 (5) ◽

pp. 332

Author(s):

Szu-Jen Wang ◽

Pei-Ming Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Kinase Inhibitors ◽

Cancer Genomics ◽

Gene Signature ◽

Migration And Invasion ◽

Advanced Hcc ◽

Telomerase Inhibitor ◽

Cell Cycle Related Gene ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug–gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.

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