Promotes Liver Cancer Cell Proliferation Research Articles

MATR3 promotes liver cancer progression by suppressing DHX58–mediated type I interferon response

MATR3 is a nuclear matrix protein implicated in various cancers; however, its specific role in tumor progression remains unclear. The study utilized the TCGA database to reveal that MATR3 expression is upregulated in liver cancer and is correlated with poor prognosis. Functionally, MATR3 promoted liver cancer cell proliferation and metastasis. Comprehensive RNA sequencing analysis showed that MATR3 significantly affected the type I IFN signaling pathway and DHX58 is a downstream target of MATR3. Further experiments showed that MATR3 bound to DHX58 mRNA through its RRM structural domain and recruited YTHDF2, an m6A reader, leading to degradation of DHX58 mRNA and suppression of the type I IFN signaling pathway. The knockout of MATR3 in liver cancer cells triggered a natural immune response that stimulated CD8+ T cells to eliminate liver cancer cells. This study demonstrated that MATR3 downregulates type I IFN signaling in liver cancer cells through m6A modification and inhibits immune cell infiltration within tumors. These findings expand our understanding of the role of MATR3 in liver cancer.

BRG1 promotes liver cancer cell proliferation and metastasis by enhancing mitochondrial function and ATP5A1 synthesis through TOMM40

ABSTRACT Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide. Brahma-related gene 1 (BRG1), as a catalytic ATPase, is a major regulator of gene expression and is known to mutate and overexpress in HCC. The purpose of this study was to investigate the mechanism of action of BRG1 in HCC cells. In our study, BRG1 was silenced or overexpressed in human HCC cell lines. Transwell and wound healing assays were used to analyze cell invasiveness and migration. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) detection were used to evaluate mitochondrial function in HCC cells. Colony formation and cell apoptosis assays were used to evaluate the effect of BRG1/TOMM40/ATP5A1 on HCC cell proliferation and apoptosis/death. Immunocytochemistry (ICC), immunofluorescence (IF) staining and western blot analysis were used to determine the effect of BRG1 on TOMM40, ATP5A1 pathway in HCC cells. As a result, knockdown of BRG1 significantly inhibited cell proliferation and invasion, promoted apoptosis in HCC cells, whereas BRG1 overexpression reversed the above effects. Overexpression of BRG1 can up-regulate MMP level, inhibit mPTP opening and activate TOMM40, ATP5A1 expression. Our results suggest that BRG1, as an oncogene, promotes HCC progression by regulating TOMM40 affecting mitochondrial function and ATP5A1 synthesis. Targeting BRG1 may represent a new and effective way to prevent HCC development.

Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

CARMIL1 regulates liver cancer cell proliferation by activating the ERK/mTOR pathway through the TRIM27/p53 axis

Capping protein regulatory factor and myosin 1 linker 1 is termed CARMIL1. CARMIL1 is involved in several physiological processes; it forms an actin filament network and plasma membrane-bound cellular projection tissues and positively regulates the cellular components and tissues. CARMIL1 exhibits important biological functions in cancer; nonetheless, these functions have not been completely explored. We aimed to investigate the novel functions of CARMIL1 in liver cancer, particularly in cell proliferation. The cell counting kit-8, 5-ethynyl-2′-deoxyuridine, Component A experiments, and subcutaneous tumor formation model suggest that CARMIL1 is central to the proliferation of liver cancer cells both in vivo and in vitro. We extracted CARMIL1 samples from The Cancer Genome Atlas Program and analyzed its enrichment. CARMIL1 regulated the pathway activity by affecting the expression of star molecular proteins of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Moreover, it influenced the proliferation ability of liver cancer cells. Western blotting suggested that CARMIL1 downregulation could affect ERK and mTOR phosphorylation. Results of the co-immunoprecipitation demonstrated that CARMIL1 binds to tripartite motif (TRIM)27, which in turn binds to p53. Subsequently, CARMIL1 can regulate p53 stability and promote its degradation through TRIM27. Additionally, CARMIL1 inhibition enhanced the sensitivity of liver cancer cells to sorafenib. Tumor growth was significantly inhibited in the group treated with sorafenib and CARMIL1, compared with the group treated with CARMIL1 alone. Sorafenib is a first-line targeted chemotherapeutic drug for hepatocellular carcinoma treatment. It increases the long-term survival of hepatocellular carcinoma by 44%. In this study, downregulated CARMIL1 combined with sorafenib significantly reduced the tumor volume and weight of the mouse subcutaneous tumor model, indicating the potential possibility of combining CARMIL1 with sorafenib in hepatocellular carcinoma treatment. In summary, CARMIL1 promotes liver cancer cell proliferation by regulating the TRIM27/p53 axis and activating the ERK/mTOR pathway.

Role of autophagy-related genes in liver cancer prognosis

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.

LINC00839 promotes malignancy of liver cancer via binding FMNL2 under hypoxia

Liver cancer is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with liver cancer. Hypoxia is a common feature of solid tumors and enhances malignant character of cancer cells. However, the exact mechanisms involved in hypoxia-driven liver cancer progression and metastasis have not been well clarified so far. The aim of this study was to investigate the contribution of long non-coding RNA (lncRNA) in hypoxia promoting liver cancer progression. We screened and revealed LINC00839 as a novel hypoxia-responsive lncRNA in liver cancer. LINC00839 expression was up-regulated in liver cancer tissues and cell lines, and the patients with high LINC00839 expression had shortened overall survival. LINC00839 further overexpressed under hypoxia and promoted liver cancer cell proliferation, migration, and invasion. Mechanistically, LINC00839 bound multiple proteins that were primarily associated with the metabolism and RNA transport, and positively regulated the expression of Formin-like protein 2 (FMNL2). LINC00839 could promote hypoxia-mediated liver cancer progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of liver cancer.

Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer

Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver cancer progression and fills the research gap in non-histone protein crotonylation function.

RNA Helicase DHX37 Facilitates Liver Cancer Progression by Cooperating with PLRG1 to Drive Superenhancer-Mediated Transcription of Cyclin D1.

This work characterizes a novel mechanism of superenhancer-driven cyclin D1 upregulation by DHX37 and PLRG1, implicating this pathway as a potential therapeutic target in hepatocellular carcinoma.

Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway

Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer.

LncRNA LOXL1-AS1 promotes liver cancer cell proliferation and migration by regulating the miR-377-3p/NFIB axis.

Liver cancer is becoming one of the most lethal malignancies due to its high incidence and mortality. Accumulating studies have indicated that long non-coding RNAs (lncRNAs) are critical regulators of the tumorigenesis and development of various types of cancer, including liver cancer. LncRNA LOXL1-antisense RNA 1 (LOXL1-AS1) has been identified as an oncogene in some types of human cancer; however, its role in liver cancer remains obscure. Reverse transcription-quantitative PCR was used to measure LOXL1-AS1 expression in liver cancer tissues and cells. Western blot, MTT, colony formation, glucose uptake and wound healing assays were used to explore the biological function of LOXL1-AS1 in liver cancer cells. Bioinformatics analysis and RNA pull-down and luciferase reporter assays were used to explore the molecular mechanism of LOXL1-AS1 in liver cancer cells. Statistical analysis was used to compare the experimental results of different groups. In the present study, LOXL1-AS1 expression was significantly upregulated in liver cancer tissues and cells compared with in normal liver tissues and cells, respectively. High LOXL1-AS1 expression was associated with poor clinical outcomes in patients with liver cancer. Furthermore, LOXL1-AS1-knockdown suppressed glucose metabolism, proliferation, migration and epithelial-mesenchymal transition (EMT) of liver cancer cells. Subsequently, LOXL1-AS1 acted as a microRNA (miR)-377-3p sponge, and nuclear factor I B (NFIB) was confirmed as the downstream target of miR-377-3p in liver cancer cells. Additionally, rescue assays suggested that NFIB overexpression countervailed the inhibitory influence of LOXL1-AS1 silencing on liver cancer cellular processes. The present study demonstrated that LOXL1-AS1 promoted glucose metabolism, proliferation, migration and EMT of liver cancer cells by sponging miR-377-3p and modulating NFIB, which may provide a novel insight for the treatment of liver cancer.

LncRNA XIST promotes liver cancer progression by acting as a molecular sponge of miR-200b-3p to regulate ZEB1/2 expression.

ObjectiveTo evaluate the predictive value of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) for survival, and determine the involvement of miRNA(miR)-200b-3p and zinc finger E-box-binding homeobox (ZEB) 1/2 in the pro-tumor effect of lncRNA XIST in liver cancer.MethodsWe evaluated lncRNA XIST expression in liver cancer tissues and cell lines by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and analyzed the correlation between its expression and overall survival of liver cancer patients by Kaplan–Meier analysis. Its effects on cell proliferation, migration, and invasion were analyzed by Cell-Counting Kit-8 and Transwell assays. The association between lncRNA XIST and miR-200b-3p, and the effects of lncRNA XIST on ZEB1/2 expression were explored using luciferase reporter assays, real-time PCR, and western blotting.ResultsThe lncRNA XIST was significantly upregulated in liver cancer, and increased lncRNA XIST expression was associated with a poor prognosis. The lncRNA XIST promoted liver cancer cell proliferation, migration, and invasion in vitro, and acted as a molecular sponge for miR-200b-3p, and also regulated the expression of ZEB1/2 via miR-200b-3p.ConclusionThe lncRNA XIST is an oncogenic lncRNA that promotes liver cancer metastasis, and its pro-metastatic phenotype can be partially attributed to the lncRNA XIST/miR-200b-3p/ZEB1/2 signaling axis.

MiR-660 promotes liver cancer cell proliferation by targeting PPP2R2A.

Liver cancer (LC) is the leading cause for tumor-related death worldwide, and microRNAs (miRs) have been demonstrated to regulate the progression of LC. In the current study, the function of miR-660 in LC cells was investigated, and the results indicated that miR-660 was highly expressed in LC tissues and cells. This increased expression promoted LC cell proliferation and increased the percentage of S phase cells, while miR-660 knockdown inhibited cell proliferation and increased the percentage of G0/G1 phase cells. A Ser/Thr phosphatase protein phosphatase 2 regulatory subunit βα (PPP2R2A) was indicated as the target of miR-660, and miR-660 could inhibit PPP2R2A levels. The luciferase reporter assay suggested that miR-660 directly bound to the 3'-untranslated region of PPP2R2A. Additionally, it was revealed that miR-660 inhibited p21 expression and promoted cyclin D1 expression, confirming that miR-660 regulated LC cell proliferation by regulating cell cycle progression. The double knockdown of miR-660 and PPP2R2A promoted LC cell proliferation, suggesting that miR-660 promoted LC proliferation by targeting PPP2R2A.

Long Noncoding RNA EBLN3P Promotes the Progression of Liver Cancer via Alteration of microRNA-144-3p/DOCK4 Signal.

BackgroundTherapy for patients with liver cancer in the advanced stage remains a great challenge, and there are very few approved treatments. Although accumulated evidence demonstrates the importance of lncRNAs in liver cancer, data on the functional roles and molecular mechanisms of endogenous bornavirus-like nucleoprotein (EBLN3P) have been rarely reported.Materials and MethodsThe bioinformatics prediction software ENCORI was used to predict the putative binding sites of EBLN3P. The regulatory roles of EBLN3P and miR-144-3p in cell proliferation, migration and invasion ability were verified by the Cell Counting Kit-8, wound healing and Transwell assays, respectively. The interactions among EBLN3P, miR-144-3p and DOCK4 were explored by a luciferase assay and Western blotting. The expression of EBLN3P and microRNA (miR)-144-3p in liver cancer tissues was quantified by reverse transcription-quantitative PCR, and the expression of dedicator of cytokinesis 4 (DOCK4) was quantified by immunohistochemical analysis.ResultsThe present results revealed that overexpression of EBLN3P or knockdown of miR-144-3p promoted liver cancer cell proliferation, migration and invasion. Bioinformatics analysis and a luciferase assay demonstrated that EBLN3P directly interacts with miR-144-3p to attenuate miR-144-3p binding to the 3ʹ-untranslated region of DOCK4. Furthermore, the mechanistic investigations showing that the miR-144-3p/DOCK4 regulatory loop was activated by knockdown of miR‐144-3p or overexpression of DOCK4 validate the roles of EBLN3P in promoting liver cancer cell proliferation, migration and invasion in vitro. Elevated levels of EBLN3P and DOCK4 and decreased miR-144-3p expression were observed in both liver cancer tissues and cell lines.ConclusionThe present study is the first to demonstrate that EBLN3P may act as a ceRNA to modulate DOCK4 expression by competitively sponging miR-144-3p, leading to the regulation of liver cancer progression, which provides new insights for liver cancer diagnosis and treatment.

Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway.

BackgroundRho-GTPases and their activators, guanine nucleotide exchange factors (GEFs), are increasingly being recognized as essential mediators of oncogenic signaling. Although it is known that P-Rex1, a member of the Dbl family of GEFs for the Rac small GTPase, contributes to the migration of cancer cells, its exact role in liver cancer and the underlying mechanisms remain unclear.Materials and MethodsPublic datasets from the Gene Expression Omnibus database (GEO) and clinical liver cancer samples were analyzed to explore the expression of P-Rex1. P-Rex1 knockdown and overexpression cell lines were established using a recombinant lentiviral transfection system. BrdU and colony formation assays were performed to determine cell viability. Migratory capacity was analyzed using a transwell migration assay and an in vitro wound-healing assay. Nude mice bearing subcutaneous xenograft tumors were established to determine the effects of P-Rex1 on tumorigenesis in vivo. The role of P-Rex1 in hepatocarcinogenesis was determined through Western blot and co-immunoprecipitation.ResultsInduced expression of endogenous P-Rex1 was identified in liver cancer tumors when compared with adjacent nonmalignant tissues from clinical data. In response to HGF treatment, P-Rex1-knockdown cells displayed reduced proliferation and migration in vitro as well as reduced xenograft tumor growth in vivo. Overexpression of P-Rex1 promoted liver cancer cell proliferation and migration. P-Rex1 primarily acts as a downstream effector of GPCR signaling. This study demonstrated that downregulation of P-Rex1 led to a significant decrease in the phosphorylation of Akt and Erk1/2 by reducing the phosphorylation of the tyrosine kinase receptor c-Met. Furthermore, a physical association between P-Rex1 and c-Met was observed after HGF treatment, suggesting that P-Rex1 may be involved in the HGF/c-Met signaling pathway.ConclusionThese results support the role of P-Rex1 as a novel player in liver cancer, which suggest that targeting P-Rex1 may provide a potential strategy for liver cancer treatment.

Circ_0000105 promotes liver cancer by regulating miR-498/PIK3R1.

A growing number of studies demonstrate that circular RNA (circRNA) has a prominent role in the regulation of numerous biological behaviors of tumor cells. The present study aimed to investigate the expression, function and molecular mechanisms of circ_0000105 in liver cancer. A quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to obtain the expressions of circ_0000105 and miR-498 in liver cancer tissues and cells. The association between the expression level of circ_0000105 and the clinicopathological characteristics of liver cancer patients was analyzed. qRT-PCR and western blotting were utilized to investigate the expression of phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) in cells. Cell counting kit-8, bromodeoxyuridine and flow cytometry assays were utilized to determine liver cancer cell proliferation and apoptosis, respectively. Bioinformatics, a luciferase reporter gene experiment and a RNA immunoprecipitation experiment were conducted to predict and confirm the targeting correlation of circ_0000105 and miR-498, as well as miR-498 and PIK3R1. Circ_0000105 was highly expressed in liver cancer tissues and cell lines. Moreover, its high expression was associated with an increase in the T stage of liver cancer patients and a low degree of tumor differentiation. Circ_0000105 overexpression promoted liver cancer cell proliferation and inhibited apoptosis, whereas knocking down circ_0000105 triggered the opposite effect. miR-498 was a downstream target of circ_0000105, inhibiting liver cancer cell proliferation and promoting apoptosis. Mechanistically, circ_0000105 indirectly up-regulated the expression of PIK3R1 by adsorbing miR-498. Circ_0000105 plays a cancer-promoting role in liver cancer by regulating the miR-498/PIK3R1 axis.

Upregulation of amphiregulin by retinoic acid and Wnt signalling promotes liver cancer cell proliferation.

Activated hepatic stellate cells promote hepatocellular carcinoma (HCC) progression. Hepatic stellate cells play a key role in retinoid metabolism, and activation of stellate cells increases retinoic acid (RA) in the liver. However, the role of RA in HCC proliferation remains unclear. We aimed to analyse the mechanism of RA in HCC proliferation. Thirty-eight patients who had undergone hepatic resection for HCCs were recruited. Paired non-tumour tissues, adjacent and distal to HCCs, were collected, and the RA levels in the tissues were analysed. The mechanisms of RA and HCC proliferation were assessed in liver cancer cell lines by protein and gene expression analyses. Early recurrence of HCC was significantly higher in patients with a higher RA concentration than in those with a lower RA concentration in tissues adjacent to HCCs (61.1% vs. 20%, p = .010). RA promoted HCC cell proliferation and activated the expression of Amphiregulin, a growth factor in hepatocarcinogenesis. The promoter of Amphiregulin contained the binding sites of the RA receptor, RXRα. Wnt signalling also activated the expression of Amphiregulin, and the RA and Wnt pathways acted synergistically to increase the expression of Amphiregulin. Furthermore, RXRα interacted with β-catenin and then translocated to the nucleus to activate Amphiregulin. An increased RA concentration in the tissues adjacent to the tumour was associated with an early recurrence of HCC. RA activated the expression of Amphiregulin, and then promoted HCC proliferation, which might partly contribute to early recurrence of HCC after hepatic resection.

Knockdown of ACTA2‑AS1 promotes liver cancer cell proliferation, migration and invasion.

Long noncoding RNAs (lncRNAs) are important regulators of various cellular and biological processes. The present study aimed to investigate the functions of a novel lncRNA, ACTA2‑AS1:4, a transcript variant of smooth muscle α‑actin 2‑antisense 1 (ACTA2‑AS1), in regulating liver cancer progression. Expression of lncRNAs in liver cancer tissues and cell lines were analyzed by reverse transcription quantitative polymerase chain reaction (RT‑qPCR). Knockdown of ACTA2‑AS1:4 expression in LM3 liver cancer cells was achieved by transfection with small interfering RNAs (siRNAs) that specifically targeted ACTA2‑AS1:4. The proliferation and cell cycle progression of ACTA2‑AS1:4‑silenced LM3 cells were determined using MTS assay and flow cytometry, respectively. A Transwell system assay was used to evaluate the migration and invasion capacities of LM3 cells transfected with ACTA2‑AS1:4 siRNA. The expression levels of major genes associated with important cellular processes were finally determined by RT‑qPCR and western blot analysis. ACTA2‑AS1:4 expression in liver cancer tissues and multiple cell lines was markedly downregulated by specific siRNAs. This inhibition of ACTA2‑AS1:4 expression significantly promoted the proliferation, cell cycle progression, migration and invasion of LM3 cells. A decrease in ACTA2‑AS1:4 expression also suppressed E‑cadherin expression, increased N‑cadherin expression, decreased caspase 3 expression and increased cyclin D1 and matrix metalloproteinase expression in liver cancer cells. Downregulation of ACTA2‑AS1:4 affects a number of key mechanisms involved in liver cancer progression. These data may be important for the future of liver cancer diagnosis and subsequent treatments.

TRIM29 prevents hepatocellular carcinoma progression by inhibiting Wnt/β-catenin signaling pathway.

TRIM29 plays an important role in many neoplasms. In this study, we aimed to elucidate its role in hepatocellular carcinoma (HCC) and explore the corresponding potential mechanism. The expression level of TRIM29 in HCC samples and hepatoma cell lines was detected. We found that TRIM29 was down-regulated in clinical HCC samples and cultured hepatoma cell lines by western blot analysis and quantitative polymerase chain reaction. In addition, we demonstrated that higher TRIM29 expression was associated with higher differentiation grade of HCC. To explore the effect of TRIM29 on hepatoma cells and its possible mechanisms, TRIM29-knockdown and overexpression cell models were constructed. The results showed that the depletion of TRIM29 promoted liver cancer cell proliferation, clone formation, migration and invasion in vitro probably through the Wnt/β-catenin signaling pathway. This study revealed the inhibitory roles of TRIM29 in HCC and the possible mechanisms.

MiRNA‑222 promotes liver cancer cell proliferation, migration and invasion and inhibits apoptosis by targeting BBC3.

The present study aimed to investigate molecular mechanisms associated with liver cancer and provide a possible therapeutic target for the treatment of liver cancer. Liver cancer patients that were diagnosed and treated at the Central Hospital of China National Petroleum Corp. were included in the present study. microRNA (miR)-222 was predicted to target B-cell lymphoma-2 (Bcl-2) binding component 3 (BBC3, also known as p53 upregulated modulator of apoptosis) by a bioinformatics analysis with TargetScan, which was verified by a dual-luciferase reporter assay system. The correlations between BBC3 and miR-222 levels and the patients' characteristics were analyzed. Furthermore, reverse transcription-quantitative polymerase chain reaction was used to assess the mRNA levels of miRNA-222 in the HCC-LM3, MHCC97H and HepG2 cell lines. HepG2 cells were then transfected with miR-222 inhibitor or miR-negative control inhibitor. Cell proliferation, apoptosis, cell cycle, migration and invasion were evaluated by an MTT assay, flow cytometry, wound healing assay and Transwell assay, respectively. BBC3 was quantified by immunofluorescence and western blot analysis, and cyclin D1, Bcl-2 and caspase-3 levels were also evaluated by western blotting. miR-222 inhibitor obviously inhibited HepG2 cell proliferation, migration, invasion, BBC3 and cyclin D1 protein expression levels and enhanced HepG2 cell apoptosis as well as the protein levels of Bcl-2 and caspase-3. miR-222 level in tumors ≥5 cm (maximum) was significantly higher compared with tumors <5 cm (maximum) and was significantly higher in metastatic tumors compared with non-metastatic tumors, while BBC3 level showed the adverse changes. The results of the present study suggested that miR-222 inhibitor exerted anti-cancer effects against liver cancer cells, probably by targeting the 3′ untranslated region (UTR) of BBC3.

MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance.

Microrchidia 2 (MORC2) is important in DNA damage repair and lipogenesis, however, the clinical and functional role of MORC2 in liver cancer remains to be fully elucidated. The aim the present study was to clarify the role of MORC2 in liver cancer. Expression profile analysis, immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were performed to evaluate the levels of MORC2 in liver cancer patient specimens and cell lines; subsequently the expression of MORC2 was suppressed or increased in liver cancer cells and the effects of MORC2 on the cancerous transformation of liver cancer cells were examined in vitro and in vivo. MORC2 was upregulated in liver cancer tissues, and the upregulation was associated with certain clinicopathologic features of patients with liver cancer. MORC2 knockdown caused marked inhibition of liver cancer cell proliferation and clonogenicity, whereas the overexpression of MORC2 substantially promoted liver cancer cell proliferation. In addition, the knockdown of MORC2 inhibited the migratory and invasive ability of liver cancer cells, whereas increased migration and invasion rates were observed in cells with ectopic expression of MORC2. In a model of nude mice, the overexpression of MORC2 promoted tumorigenicity and markedly enhanced pulmonary metastasis of liver cancer. Furthermore, MORC2 regulated apoptosis and its expression level had an effect on the sensitivity of liver cancer cells to doxorubicin, 5-fluorouracil and cisplatin. Mechanically, MORC2 modulated the mitochondrial apoptotic pathway, possibly in a p53-dependent manner, and its dysregulation also resulted in the abnormal activation of the Hippo pathway. For the first time, to the best of our knowledge, the present study confirmed that MORC2 was a novel oncogene in liver cancer. These results provide useful insight into the mechanism underlying the tumorigenesis and progression of liver cancer, and offers clues into potential novel liver cancer therapies.