C1orf61 promotes hepatocellular carcinoma metastasis and affects the therapeutic response to sorafenib

Abstract Background C1orf61 is a specific transcriptional activator that is highly up-regulated during weeks 4–9 of human embryogenesis, the period in which most organs develop. We have previously demonstrated that C1orf61 acts as a tumor activator in human hepatocellular carcinoma (HCC) tumorigenesis and metastasis. However, the underlying molecular mechanisms of tumor initiation and progression in HCC remain obscure. Methods In this study, we demonstrated that the pattern of C1orf61 expression was closely correlated with metastasis in liver cancer cells. Gene expression profiling analysis indicated that C1orf61 regulated diverse genes related to cell growth, migration, invasion and epithelial-mesenchymal transition (EMT). Results Results showed that C1orf61 promotes hepatocellular carcinoma metastasis by inducing cellular EMT in vivo and in vitro. Moreover, C1orf61-induced cellular EMT and migration are involved in the activation of the STAT3 and Akt cascade pathways. We also found that C1orf61 was associated with HBV infection-induced cell migration in HCC. In addition, C1orf61 expression improved the efficacy of the anticancer therapy sorafenib in HCC patients. For the first time, we report a regulatory pathway by which C1orf61 promoted cancer cell metastasis and regulated the therapeutic response to sorafenib. Conclusions These findings increased our understanding of the molecular events that regulate metastasis and treatment in HCC.

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KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3

International Journal of Molecular Sciences ◽

10.3390/ijms23010104 ◽

2021 ◽

Vol 23 (1) ◽

pp. 104

Author(s):

Yanhong Wang ◽

Na Li ◽

Yanping Zheng ◽

Anqing Wang ◽

Chunlei Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Adaptor Protein ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Macromolecular Protein ◽

Carcinoma Metastasis

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

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Reexpression of Let-7g MicroRNA Inhibits the Proliferation and Migration via K-Ras/HMGA2/Snail Axis in Hepatocellular Carcinoma

BioMed Research International ◽

10.1155/2014/742417 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Ke-ji Chen ◽

Ying Hou ◽

Kui Wang ◽

Jun Li ◽

Yong Xia ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Mtt Method ◽

Carcinoma Cell Lines ◽

And Migration

Let-7 family microRNAs have been reported to be downregulated in human hepatocellular carcinoma in comparison with normal hepatic tissues. Among them, let-7g was identified as the lowest expression using real-time RT-PCR. However, the mechanism by which let-7g works in hepatocellular carcinoma remains unknown. Here, in our present study, we have had let-7g reexpressedin vitroin hepatocellular carcinoma cell lines MHCC97-H and HCCLM3 via transfection. The proliferation after reexpression of let-7g was assayed using MTT method; the migration and invasion after restoration were detected by wound-healing and Transwell assay, respectively. We found using Western-blotting that let-7g can regulate epithelial-mesenchymal transition (EMT) by downregulating K-Ras and HMGA2A after reexpresssion. Xenografted nude mice were used to observe whether or not reexpression of let-7g could have potential therapeutic ability.In vivo, to observe the association with let-7g expression and overall prognosis, 40 paired cases of hepatocellular carcinoma were analyzed using in situ hybridization (ISH). It was found that reexpression of let-7g can inhibit the proliferation, migration, and invasion significantly, and that low expression of let-7g was significantly associated with poorer overall survival. Taken together, let-7g could be used as a promising therapeutic agentin vivoin the treatment of hepatocellular carcinoma at the earlier stage.

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Prognostic value of Mortalin correlates with roles in epithelial–mesenchymal transition and angiogenesis in lung adenocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgab081 ◽

2021 ◽

Author(s):

Ziqi Meng ◽

Rui Zhang ◽

Xuwei Wu ◽

Meihua Zhang ◽

Songnan Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Malignant Phenotype ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

In Vivo Experiments ◽

And Migration

Abstract Mortalin is involved in the malignant phenotype of many cancers. However, the specific molecular mechanisms involving Mortalin in lung adenocarcinoma remain unclear. In this study, we showed that both Mortalin mRNA and protein are overexpressed in lung adenocarcinoma. In addition, Mortalin overexpression was positively-correlated with poor overall survival. In vitro experiments showed that Mortalin silencing inhibited the proliferation, colony formation, and migration abilities of A549 and H1299 cells. Mortalin promotes EMT progression, angiogenesis, and tumor progression by activating the Wnt/β-catenin signaling pathway In vivo experiments further confirmed that Mortalin promoted malignant progression of lung adenocarcinoma. Taken together, our data suggest that Mortalin represents an attractive prognostic marker and therapeutic target in lung adenocarcinoma patients.

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Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3β/Snail Signaling Pathway in Hepatocellular Carcinoma

Frontiers in Pharmacology ◽

10.3389/fphar.2021.610158 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jialing Sun ◽

Weicong Chen ◽

Bin Wen ◽

Mingjia Zhang ◽

Haitao Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Mice Model ◽

Mesenchymal Transition ◽

Signaling Axis ◽

Xenograft Mice Model ◽

Gsk 3Β

Hepatocellular carcinoma (HCC) is among the most usual cancers globally. In China, Biejiajian pill (BJJP), Traditional Chinese Medicine clinical prescription, is broadly utilized for the prevention and therapy of HCC. However, the mechanisms by which BJJP exerts its effects on the prevention of tumor invasion and metastasis are still largely unknown. In this study, in vitro multiple hepatic cancer cell lines and an in vivo xenograft mice model were used to validate the preventive effects and molecular mechanisms of BJJP in HCC. We established that BJJP significantly repressed the proliferation, metastasis and infiltration of HCC cells. Furthermore, BJJP remarkably suppressed HCC cell migration, as well as invasion via epithelial-mesenchymal transition (EMT) by modulating Snail expression, which was associated with the repression of Akt/GSK-3β/Snail signaling axis activation. In vivo HCC xenograft results indicated that BJJP delayed HCC development and efficiently inhibited lung metastasis. Taken together, BJJP was shown to be an effective therapeutic agent against HCC through repression of the Akt/GSK-3β/Snail signaling cascade and EMT.

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Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000495825 ◽

2018 ◽

Vol 51 (5) ◽

pp. 2065-2072 ◽

Cited By ~ 3

Author(s):

Wei Bian ◽

Hongfei Zhang ◽

Miao Tang ◽

Shaojun Zhang ◽

Lichao Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Metastatic Progression ◽

Mesenchymal Transition ◽

Reporter Assays

Background/Aims: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. Methods: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. Results: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3’-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. Conclusion: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

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Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

Experimental Biology and Medicine ◽

10.1177/1535370218762514 ◽

2018 ◽

Vol 243 (7) ◽

pp. 645-654 ◽

Cited By ~ 3

Author(s):

Yi-Quan Yan ◽

Juan Xie ◽

Jing-Fu Wang ◽

Zhao-Feng Shi ◽

Xiang Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Unfavorable Clinical Outcome ◽

Metastasis Models ◽

Tumor Growth And Metastasis

Hepatocellular carcinoma (HCC) is one of the most malignant diseases worldwide. The unfavorable clinical outcome and poor prognosis are due to high rates of recurrence and metastasis after treatments. Some scholars of traditional Chinese medicine suggested that endogenous wind-evil had played an important role in metastasis of malignant tumor. Therefore, the drug of dispelling wind-evil could be used to prevent cancer metastasis and improve the poor prognosis. So we wondered whether Scorpion, one of the most important wind calming drugs, has antitumor effect especially in epithelial–mesenchymal transition (EMT) and metastasis of HCC in this research. We found that Scorpion-medicated serum could inhibit proliferation, induce apoptosis, and decrease migration and invasion capacity of Hepa1-6 cells in vitro. Meanwhile, we observed that water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT, which is characterized by increased epithelial marker E-cadherin expression and decreased mesenchymal markers N-cadherin and Snail expression following Scorpion treatment both in vitro and in vivo. These results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis. Impact statement The unfavorable clinical outcome and poor prognosis of hepatocellular carcinoma (HCC) are due to high rates of recurrence and metastasis after treatments. Here we found Scorpion, one of the most important wind calming drugs, has antitumor effect. Scorpion-medicated serum inhibited the proliferation, induced apoptosis, and decreased migration and invasion capacity of Hepa1-6 cells in vitro. Water decoction of Scorpion restrained tumor growth and metastasis in nude mouse of HCC metastasis models. Further experiments showed that Scorpion could suppress EMT of HCC both in vitro and in vivo. Our results suggested that the Scorpion could inhibit Hepa1-6 cells’ invasion and metastasis in part by reversing EMT and providing a possible potential approach for preventing HCC metastasis.

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Effects of GLS1 on the epithelial-mesenchymal transition of hepatocellular carcinoma in vitro and in vivo

Translational Cancer Research ◽

10.21037/tcr.2018.01.14 ◽

2018 ◽

Vol 7 (1) ◽

pp. 97-108 ◽

Cited By ~ 2

Author(s):

Yajuan Cao ◽

Binghua Li ◽

Xianbiao Shi ◽

Hongyan Wu ◽

Chen Yan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

Cell Death and Disease ◽

10.1038/s41419-020-03259-2 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Hongli Li ◽

Qingjie Mu ◽

Guoxin Zhang ◽

Zhixin Shen ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Tumor Development ◽

Biological Significance ◽

Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

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Epigenetic silencing of CDKN1A and CDKN2B by SNHG1 promotes the cell cycle, migration and epithelial-mesenchymal transition progression of hepatocellular carcinoma

Cell Death and Disease ◽

10.1038/s41419-020-03031-6 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Bei Li ◽

Ang Li ◽

Zhen You ◽

Jingchang Xu ◽

Sha Zhu

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Luciferase Assay ◽

Bioinformatics Analyses ◽

Mesenchymal Transition ◽

Rna Immunoprecipitation

Abstract Enhanced SNHG1 (small nucleolar RNA host gene 1) expression has been found to play a critical role in the initiation and progression of hepatocellular carcinoma (HCC) with its detailed mechanism largely unknown. In this study, we show that SNHG1 promotes the HCC progression through epigenetically silencing CDKN1A and CDKN2B in the nucleus, and competing with CDK4 mRNA for binding miR-140-5p in the cytoplasm. Using bioinformatics analyses, we found hepatocarcinogenesis is particularly associated with dysregulated expression of SNHG1 and activation of the cell cycle pathway. SNHG1 was upregulated in HCC tissues and cells, and its knockdown significantly inhibited HCC cell cycle, growth, metastasis, and epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Chromatin immunoprecipitation and RNA immunoprecipitation assays demonstrate that SNHG1 inhibit the transcription of CDKN1A and CDKN2B through enhancing EZH2 mediated-H3K27me3 in the promoter of CDKN1A and CDKN2B, thus resulting in the de-repression of the cell cycle. Dual-luciferase assay and RNA pulldown revealed that SNHG1 promotes the expression of CDK4 by competitively binding to miR-140-5p. In conclusion, we propose that SNHG1 formed a regulatory network to confer an oncogenic function in HCC and SNHG1 may serve as a potential target for HCC diagnosis and treatment.

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HEG1 indicates poor prognosis and promotes hepatocellular carcinoma invasion, metastasis, and EMT by activating Wnt/β-catenin signaling

Clinical Science ◽

10.1042/cs20190225 ◽

2019 ◽

Vol 133 (14) ◽

pp. 1645-1662 ◽

Cited By ~ 7

Author(s):

Yan-rong Zhao ◽

Ji-long Wang ◽

Cong Xu ◽

Yi-ming Li ◽

Bo Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Heart Development ◽

Poor Prognosis ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Intrahepatic Metastasis ◽

Mesenchymal Transition

Abstract Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.

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