Targeting TRIM54/Axin1/β-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Zhu J
PROVIDER: S-EPMC8695909 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) metastasis is largely responsible for HCC-associated recurrence and mortality. We aimed to identify metastasis-related long non-coding RNAs (lncRNAs) to understand the molecular mechanism of HCC metastasis. We first identified that miR-1258 was downregulated in HCC tissues both in The Cancer Genome Atlas (TCGA) and Sun Yat-sen University Cancer Center (SYSUCC) dataset. MiR-1258 expression negatively correlated with recurrence-free survival and overall survival of HCC patients. MiR-1258 overexpression inhibited migration and invasion of HCC cells both in vitro and in vivo, whereas miR-1258 downregulation promoted cell metastasis. Luciferase assays verified direct binding of miR-1258 to Smad2 and Smad3, thereby attenuating TGF-β/Smad signaling. We further established that lncRNA LINC01278 was a negative regulator of miR-1258. In vivo and in vitro assays demonstrated that LINC01278-mediated HCC metastasis was dependent on miR-1258 expression. Furthermore, miR-1258 downregulation in turn increased LINC01278 expression. We also observed that TCF-4 could bind to the LINC01278 promoter site. In addition, LINC01278 downregulation decreased migration and invasion of HCC cells induced by β-catenin and TGF-β1 both in vitro and in vivo. We uncovered a novel mechanism for β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 feedback loop activation in HCC metastasis, and the study indicated that LINC01278 could serve as a therapeutic target for HCC metastasis.
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Project description:β-Adrenergic receptor (β-AR) signalling is strongly associated with tumour progression by the coupling of β-ARs with either a G protein or β-arrestin; however, the related mechanism underlying hepatocellular carcinoma (HCC) metastasis is not clear. Here, we reveal that the transcription factor Y-box binding protein 1 (YB-1) interacts with β2-adrenergic receptor (β2-AR) following stimulation with the agonist isoproterenol (ISO). Clinicopathological analysis demonstrated that β2-AR is significantly correlated with YB-1, which favours the progression of HCC. The binding of YB-1 with β2-AR resulted in YB-1 phosphorylation at serine 102 (S102) via the β-arrestin-1-dependent activation of the PI3K/AKT pathway, followed by the translocation of YB-1 to the nucleus to carry out its tumour-related function. β2-AR-mediated activation of YB-1 facilitated epithelial-to-mesenchymal transition (EMT) and HCC metastasis. The interference of YB-1 expression significantly attenuated liver tumour metastasis induced by chronic stress. Analysis of the transcriptional profile and chromatin immunoprecipitation (ChIP) identified β-catenin as a crucial target of YB-1. Our results unveiled a novel β2-AR-mediated regulatory axis in HCC metastasis that might be helpful for the development of HCC therapeutics.
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Project description:Long non-coding RNAs (lncRNAs) are critical drivers and suppressors of human hepatocellular carcinoma (HCC). The downregulation of transmembrane protein 220 antisense RNA 1 (TMEM220-AS1) is correlated with poor prognosis in HCC. Nevertheless, the role of TMEM220-AS1 in HCC and the underlying mechanism remains unclear. In this study, TMEM220-AS1 levels were markedly reduced in HCC tissues compared with noncancerous tissues. TMEM220-AS1 downregulation was confirmed in HCC cell lines. TMEM220-AS1 expression was associated with tumor stage, venous infiltration, tumor size, and survival of HCC patients. TMEM220-AS1 overexpression suppressed the migration, invasion, and proliferation of HCC cells. Interestingly, ectopic expression of TMEM220-AS1 increased TMEM220 levels in HCC cells. Decreased TMEM220 levels were observed in HCC tissues and cell lines. TMEM220 expression was positively correlated with TMEM220-AS1 levels in HCC tissue samples and TMEM220 downregulation was significantly correlated with reduced patient survival. TMEM220 overexpression suppressed HCC cell proliferation and mobility. TMEM220 knockdown eliminated the suppressive effect of TMEM220-AS1 in HCCLM3 cells. Mechanistically, TMEM220 overexpression reduced the nuclear accumulation of β-catenin and decreased MYC, Cyclin D1, and Snail1 mRNA levels in HCCLM3 cells. BIO, a GSK3β inhibitor, eliminated TMEM220-induced Wnt/β-catenin pathway inactivation and inhibited HCC cell proliferation and mobility. In conclusion, TMEM220-AS1 and TMEM220 were expressed at low levels in HCC patients. TMEM220-AS1 inhibited the malignant behavior of HCC cells by enhancing TMEM220 expression and subsequently inactivating the Wnt/β-catenin pathway.
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Project description:5-Hydroxytryptamine (5-HT), a neurotransmitter and vasoactive factor, has been reported to promote proliferation of serum-deprived hepatocellular carcinoma (HCC) cells but the detailed intracellular mechanism is unknown. As Wnt/β-catenin signalling is highly dysregulated in a majority of HCC, this study explored the regulation of Wnt/β-catenin signalling by 5-HT. The expression of various 5-HT receptors was studied by quantitative real-time polymerase chain reaction (qPCR) in HCC cell lines as well as in 33 pairs of HCC tumours and corresponding adjacent non-tumour tissues. Receptors 5-HT1D (21/33, 63.6%), 5-HT2B (12/33, 36.4%) and 5-HT7 (15/33, 45.4%) were overexpressed whereas receptors 5-HT2A (17/33, 51.5%) and 5-HT5 (30/33, 90.1%) were reduced in HCC tumour tissues. In vitro data suggests 5-HT increased total β-catenin, active β-catenin and decreased phosphorylated β-catenin protein levels in serum deprived HuH-7 and HepG2 cells compared to control cells under serum free medium without 5-HT. Activation of Wnt/β-catenin signalling was evidenced by increased expression of β-catenin downstream target genes, Axin2, cyclin D1, dickoppf-1 (DKK1) and glutamine synthetase (GS) by qPCR in serum-deprived HCC cell lines treated with 5-HT. Additionally, biochemical analysis revealed 5-HT disrupted Axin1/β-catenin interaction, a critical step in β-catenin phosphorylation. Increased Wnt/β-catenin activity was attenuated by antagonist of receptor 5-HT7 (SB-258719) in HCC cell lines and patient-derived primary tumour tissues in the presence of 5-HT. SB-258719 also reduced tumour growth in vivo. This study provides evidence of Wnt/β-catenin signalling activation by 5-HT and may represent a potential therapeutic target for hepatocarcinogenesis.
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Project description:Lung cancer is a leading cause of cancer-related mortality worldwide and poor prognosis remains a major problem encountered in its treatment. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has been recently implicated in the tumorigenesis and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of YTHDF2 in the regulation of lung adenocarcinoma (LUAD) progression remain elusive. Here we report that YTHDF2 expression was significantly increased in lung adenocarcinoma than in adjacent normal tissues. YTHDF2 knockdown drastically inhibited cell proliferation, colony formation, and migration in vitro, and the opposite proved true when YTHDF2 was overexpressed. In addition, YTHDF2 attenuation significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in lung adenocarcinoma. We further confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promotes AXIN1 RNA decay and subsequently activates the Wnt/β-catenin signaling. Knockout of AXIN1 can sufficiently rescue the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. Collectively, our results uncovered YTHDF2-mediated regulation of the AXIN1/Wnt/β-catenin signaling that contributes to LUAD tumorigenesis, and thus provided insight into the mechanisms underlying lung adenocarcinoma progression.
2021-05-19 | GSE161090 | GEO
Project description:Accumulating evidences indicate that microRNAs play a vital role in regulating tumor progression. However, the roles of miR-148b in hepatocellular carcinoma (HCC) are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 40 pairs of human HCC tissues. Further, the deregulated miR-148b was significantly correlated with larger tumor size, more tumor number, metastasis and worse prognosis in HCC. Overexpression of miR-148b inhibited HCC HepG2 cells proliferation and tumorigenicity. Further, miR-148b induced cells apoptosis by activating caspase- 3 and caspase-9, and induced S phase arrest by regulating cyclinD1 and p21, and also inhibited cell invasion. Data from the dual-luciferase reporter gene assay showed that WNT1 was a direct target of miR-148b, and overexpressed WNT1 inversely correlated with miR-148b levels in HCC tissues. Silencing of WNT1 inhibited the growth of HCC cells, and also induced cells apoptosis and inhibited invasion, which is consistent with the effects of miR-148b overexpression. MiR-148b downregulated expression of WNT1, β-catenin and C-myc, while upregulated E-cadherin expression. We conclude that the frequently downregulated miR-148b can regulate WNT1/β-catenin signalling pathway and function as a tumor suppressor in HCC. These findings suggest that miR-148b may serve as a novel therapeutic target for HCC.
| S-EPMC4310092 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) represents a high-fatality cancer with a 5-year survival of 22%. The Wnt/β-catenin signaling pathway presents as one of the most upregulated pathways in HCC. However, it has so far not been targetable in the clinical setting. Therefore, studying new targets of this signaling cascade from a therapeutic aspect could enable reversal, delay, or prevention of hepatocarcinogenesis. Although enormous advancement has been achieved in HCC research and its therapeutic management, since HCC often occurs in the context of other liver diseases such as cirrhosis leading to liver dysfunction and/or impaired drug metabolism, the current therapies face the challenge of safely and effectively delivering drugs to the HCC tumor site. In this review, we discuss how a targeted nano drug delivery system could help minimize the off-target toxicities of conventional HCC therapies as well as enhance treatment efficacy. We also put forward the current challenges in HCC nanomedicine along with some potential therapeutic targets from the Wnt/β-catenin signaling pathway that could be used for HCC therapy. Overall, this review will provide an insight to the current advances, limitations and how HCC nanomedicine could change the landscape of some of the undruggable targets in the Wnt/β-catenin pathway.
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Project description:Rapid tumor progression, metastasis, and diagnosis in advanced stages of disease are the main reasons for the short survival time and high mortality rate of patients with hepatocellular carcinoma (HCC). Ephrin A4 (EFNA4), the ligand of the EPH family, participates in the development of blood vessels and epithelium by regulating cell migration and rejection. In our study, based on bioinformatics analyses, we found that EFNA4 was highly expressed and led to poor prognosis in patients with HCC. We demonstrated that overexpression of EFNA4 significantly promoted HCC cell proliferation and migration in vivo or in vitro. In addition, knockdown of EFNA4 inhibited the proliferation and migration of HCC cells. Furthermore, EFNA4 was found to directly interact with EPHA2 and promote its phosphorylation at Ser897, followed by recruitment of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) and activation of the glycogen synthase kinase-3beta (GSK3β)/β-catenin signaling pathway. Moreover, overexpression of β-catenin further promoted the expression of PIK3R2, which formed a positive feedback loop. The results revealed that abnormal expression of EFNA4 is the main switch of the PIK3R2/GSK3β/β-catenin loop that influenced the proliferation and migration of HCC cells and suggest that EFNA4 is a potential prognostic marker and a prospective therapeutic target in patients with HCC.
| S-EPMC8397841 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide. MiR-371 has recently emerged as an important regulator in tumorigenesis, and may serve as a biomarker for malignant tumors. We transfected miR-371 or its inhibitor in two human HCC cell lines, then used 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, soft agar colony formation, and transwell migration assays to evaluate the effects on cell proliferation, migration, and invasion. We found that miR-371 was positively correlated with HCC metastasis and poor prognosis in the inflicted patients, and the high expression of miR-371 was promoted, whereas a low level of miR-371 depressed cell proliferation and invasion. We found PTEN to be a direct target of miR-371. The overexpression or knockdown of PTEN exhibited the opposite effects from those of miR-371 on cell proliferation and migration. Our study demonstrates that miR-371 promotes proliferation and metastasis in HCC by targeting PTEN. [BMB Reports 2019; 52(5): 312-317].
| S-EPMC6549920 | biostudies-literature
Project description:BackgroundKindlin-2 is a member of the focal adhesion protein family that regulates invasion and metastasis in multiple malignancies; however, little is known about the role of Kindlin-2 in hepatocellular carcinoma (HCC) progression.MethodsImmunohistochemistry was used to investigate Kindlin-2 expression in 177 pairs of human HCC and adjacent liver tissue samples. The role of Kindlin-2 in the in vitro invasion and migration of HCC cell lines was evaluated in MHCC97H, LM3 and SMMC7721 cells. Microarray expression analysis was applied to explore the molecular mechanism through which Kindlin-2 promoted HCC progression. Quantitative real-time PCR and Western blotting were performed to verify the microarray results.ResultsHigh Kindlin-2 expression was found to significantly correlate with aggressive HCC clinicopathological features including tumor encapsulation, microvascular invasion, extrahepatic metastasis and poor prognosis. In vitro, Kindlin-2 knockout or knockdown inhibited HCC cell adhesion, migration and invasion, while ectopic Kindlin-2 expression promoted these processes. Importantly, Kindlin-2 activated Wnt/β-catenin signaling and increased β-catenin expression, especially levels of non-phosphorylated β-catenin, as well as two Wnt/β-catenin signaling pathway targets, Axin2 and MMP7. Kindlin-2 also induced a change in the expression profile of HCC cells, suggesting the cells underwent epithelial-mesenchymal transition. For example, the expression of the epithelial marker E-cadherin was downregulated, while the mesenchymal markers Vimentin, N-cadherin and Snail were upregulated.ConclusionKindlin-2 promotes HCC invasion, metastasis and epithelial-mesenchymal transition through Wnt/β-catenin signaling.
| S-EPMC5623973 | biostudies-literature