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BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

ABSTRACT: Basic leucine zipper and W2 domain 2 (BZW2), also known as 5MP1, is a protein related to translation regulation. Evidence from previous studies indicates that BZW2 is involved in tumorigenesis in several cancers. However, little is known about the role of BZW2 in hepatocellular carcinoma (HCC). In this study, we first analyzed the gene expression profile of BZW2 in multiple HCC datasets. Next, we explored the biological effects of BZW2 in HCC cell lines. BZW2 was overexpressed in different HCC cohorts. Multivariate analysis confirmed that increased BZW2 expression is an independent prognostic indicator of shorter overall survival. BZW2 coexpressed genes were mainly enriched in the biological processes of ribonucleoprotein complex biogenesis, rRNA metabolism, translational initiation, and negative regulation of metabolic processes. BZW2 depletion reduced proliferation, clonality, and invasion and increased apoptosis in MHCC97-H cells. Furthermore, BZW2 overexpression or knockdown enhanced or impaired c-Myc expression, respectively. Overall, these findings identified BZW2 as a biomarker of HCC and provided novel insight that the effect of BZW2 on the translatome is a potential mechanism that promotes HCC progression via the c-Myc pathway.

SUBMITTER: Li G

PROVIDER: S-EPMC8317536 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

Li Guoxiong G Lu Anqian A Chen Anna A Geng Shuang S Xu Yu Y Chen Xin X Yang Jin J

Journal of Cancer 20210622 17

Basic leucine zipper and W2 domain 2 (BZW2), also known as 5MP1, is a protein related to translation regulation. Evidence from previous studies indicates that BZW2 is involved in tumorigenesis in several cancers. However, little is known about the role of BZW2 in hepatocellular carcinoma (HCC). In this study, we first analyzed the gene expression profile of BZW2 in multiple HCC datasets. Next, we explored the biological effects of BZW2 in HCC cell lines. BZW2 was overexpressed in different HCC c ...[more]

PMID: 34335929

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Project description:ObjectivesDystrobrevin beta (DTNB) is a constituent of the dystrophin-associated protein complex (DPC). Our previous RNA sequencing (RNA-seq) study revealed that knockdown of the oncogenic long noncoding RNA (lncRNA) HOXD cluster antisense RNA 1 (HOXD-AS1) in hepatocellular carcinoma (HCC) cells could reduce the expression levels of DTNB. However, the association between DTNB and HCC remains uncertain.MethodsThe upregulation of DTNB in HCC cell lines and the regulatory effect of HOXD-AS1 on its expression were verified using quantitative real-time PCR (qRT-PCR). The potential clinical significance, biological functions and underlying mechanisms of DTNB in HCC were investigated through bioinformatics analysis. The high expression of DTNB was validated in HCC tissues, and its biological function in HCC was investigated by performing loss-of-function assays in vitro.ResultsDTNB was highly expressed in HCC cells and was positively regulated by the lncRNA HOXD-AS1 in several HCC cell lines. The upregulation of DTNB was significantly associated with T stage, histologic grade, tumour status, adjacent hepatic tissue inflammation, alpha-fetoprotein (AFP) level, and unfavorable prognosis, serving as an independent risk indicator associated with overall survival with substantial diagnostic and prognostic implications for HCC. DTNB was also closely linked to immune cell infiltration, immunotherapy, and sensitivity to anti-HCC drugs. Genes co-expressed with DTNB in HCC were identified, and functional enrichment analysis indicated that DTNB may function in HCC by regulating the cell cycle. A potential ceRNA (competing endogenous RNA) regulatory axis of HOXD-AS1/miR-139-3p/DTNB in HCC was predicted and validated. The high expression of DTNB was validated in our HCC cohort and loss-of-function assays revealed that DTNB knockdown can suppress the proliferation, migration, and invasion of HCC cells and trigger cell cycle arrest at the G0/G1 phase.ConclusionsDTNB, a downstream target of the lncRNA HOXD-AS1, has potential utility as a prognostic biomarker and a target for the treatment of HCC.

Project description:Hepatocellular carcinoma (HCC) is a global health problem. Its incidence and mortality are increasing. Exploring novel therapeutic targets against HCC is important and urgent. We here explored the expression and potential function of Gαi2 (G protein subunit alpha i2) in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database shows that the number of Gαi2 transcripts in HCC tissues is significantly higher than that in the normal liver tissues. Moreover, Gαi2 overexpression in HCC correlates with poor prognosis of the patients. Gαi2 mRNA and protein expression are also elevated in local HCC tissues and different human HCC cells. In patient-derived primary HCC cells and immortalized HepG2 cells, Gαi2 silencing (by targeted shRNA) or knockout (KO, by the dCas9-sgRNA method) largely suppressed cell proliferation and motility, while inducing cell cycle arrest and caspase-apoptosis activation. Moreover, Gαi2 silencing or KO-induced reactive oxygen species (ROS) production and oxidative injury in primary and HepG2 HCC cells. Whereas different antioxidants ameliorated Gαi2-shRNA-induced anti-HCC cell activity. Using a lentiviral construct, Gαi2 overexpression further augmented proliferation and motility of primary and immortalized HCC cells. Further studies revealed that the binding between the transcription factor early growth response zinc finger transcription factor 1 (EGR1) and Gαi2 DNA promoter was significantly increased in HCC tissues and cells. In vivo, intratumoral injection of Gαi2 shRNA adeno-associated virus significantly hindered HCC xenograft growth in nude mice. Moreover, the growth of Gαi2-KO HCC xenografts in the nude mice was remarkably slow. Gαi2 depletion, oxidative injury, and apoptosis induction were detected in Gαi2-silenced or Gαi2-KO HCC xenografts. Together, overexpressed Gαi2 is required for HCC cell growth in vitro and in vivo, representing as a novel and promising diagnosis marker and therapeutic target of HCC.

Project description:BackgroundLong non-coding RNAs (lncRNAs) possess significant regulatory functions in multiple biological and pathological processes, especially in cancer. Dysregulated lncRNAs in hepatocellular carcinoma (HCC) and their therapeutic applications remain unclear.MethodsDifferentially expressed lncRNA profile in HCC was constructed using TCGA data. LINC00958 expression level was examined in HCC cell lines and tissues. Univariate and multivariate analyses were performed to demonstrate the prognostic value of LINC00958. Loss-of-function and gain-of-function experiments were used to assess the effects of LINC00958 on cell proliferation, motility, and lipogenesis. Patient-derived xenograft model was established for in vivo experiments. RNA immunoprecipitation, dual luciferase reporter, biotin-labeled miRNA pull-down, fluorescence in situ hybridization, and RNA sequencing assays were performed to elucidate the underlying molecular mechanisms. We developed a PLGA-based nanoplatform encapsulating LINC00958 siRNA and evaluated its superiority for systemic administration.ResultsWe identified a lipogenesis-related lncRNA, LINC00958, whose expression was upregulated in HCC cell lines and tissues. High LINC00958 level independently predicted poor overall survival. Functional assays showed that LINC00958 aggravated HCC malignant phenotypes in vitro and in vivo. Mechanistically, LINC00958 sponged miR-3619-5p to upregulate hepatoma-derived growth factor (HDGF) expression, thereby facilitating HCC lipogenesis and progression. METTL3-mediated N6-methyladenosine modification led to LINC00958 upregulation through stabilizing its RNA transcript. A PLGA-based nanoplatform loaded with si-LINC00958 was developed for HCC systemic administration. This novel drug delivery system was controlled release, tumor targeting, safe, and presented satisfactory antitumor efficacy.ConclusionsOur results delineate the clinical significance of LINC00958 in HCC and the regulatory mechanisms involved in HCC lipogenesis and progression, providing a novel prognostic indicator and promising nanotherapeutic target.

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BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

Publications

BZW2/5MP1 acts as a promising target in hepatocellular carcinoma.

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