Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

Jin, Young–Joo; Byun, Seyoun; Han, Seonggyun; Chamberlin, J. Edward; Kim, Dong-Wook; Kim, Min Jung; Lee, Younghee

doi:10.1186/s12920-019-0635-z

Cited by 15 publications

(12 citation statements)

References 64 publications

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“…CHST4 expression was found to be related to viral gene expression, and thus, low CHST4 expression may promote HBV expression and replication in HCC, thereby increasing chromosomal instability and tumor cell proliferation, as reported previously (6). We also discovered that CHST4 participates in ribonucleoprotein complex biogenesis, RNA splicing, and mRNA metabolic process, and these biological processes have previously been implicated in HCC development (50,51). Moreover, ribosome biogenesis and mutations of ribosome genes were previously shown to be related to progression of various tumors (52,53).…”

Section: Discussionsupporting

confidence: 77%

Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors

et al. 2020

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Carbohydrate sulfotransferase 4 (CHST4) plays an important role in lymphocyte homing and is abnormally expressed in several cancer types; however, its precise function in tumor development and progression is unknown. Here we confirm that CHST4 is aberrantly expressed in various tumor subtypes. In particular, we found that CHST4 expression was downregulated in hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) tumors compared to paired normal tissue. We also showed that CHST4 overexpression inhibited the proliferation and metastasis of HCC cells in vitro. Clinically, CHST4 was identified as an independent prognostic factor for HBV-HCC patients. We further illuminated the anti-tumor role and mechanism of CHST4 in HBV-HCC by constructing a FENDRR-miR-10b-5p-CHST4 competing endogenous RNA network. We found that downregulation of CHST4 expression may promote HBV expression and regulate ribonucleoprotein complex biogenesis to promote malignant behaviors in HBV-HCC. CHST4 may also recruit CD4+ T cells, macrophages, dendritic cells, and neutrophils into the tumor microenvironment to inhibit the progression of HBV-HCC. Overall, our findings suggest that CHST4 acts as a tumor suppressor in HCC-HBV and represents a potential diagnostic and therapeutic target.

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Section: Discussionsupporting

confidence: 77%

Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors

et al. 2020

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“…However, timely and effective translation of these novel molecular findings to the clinic hinges on the ability to classify patients based on the molecular features of their tumors and tailor their therapy accordingly. Although some alternative splicing pathways may be linked strongly to the etiology of HCC, 140 others may be related to the presence of cirrhosis and otherwise independent of the underlying major risk factor. 141 As such, detecting and modulating alternative splicing events at the premalignant stage also could be used as an approach for HCC prevention.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing in Hepatocellular Carcinoma

Lee

Alcedo

Kim

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Alternative splicing controls key metabolic pathways important for liver development and hepatocyte homeostasis. Global changes in RNA binding proteins yield novel tumor-associated transcripts and protein isoforms in hepatocellular carcinoma. Studies addressing these mechanisms illuminate new diagnostic, prognostic, and therapeutic targets for hepatocellular carcinoma. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer cases, with more than 850,000 new diagnoses per year globally. Recent trends in the United States have shown that liver cancer mortality has continued to increase in both men and women, while 5year survival remains below 20%. Understanding key mechanisms that drive chronic liver disease progression to HCC can reveal new therapeutic targets and biomarkers for early detection of HCC. In that regard, many studies have underscored the importance of alternative splicing as a source of novel HCC prognostic markers and disease targets. Alternative splicing of pre-mRNA provides functional diversity to the genome, and endows cells with the ability to rapidly remodel the proteome. Genes that control fundamental processes, such as metabolism, cell proliferation, and apoptosis, are altered globally in HCC by alternative splicing. This review highlights the major splicing factors, RNA binding proteins, transcriptional targets, and signaling pathways that are of key relevance to HCC. We highlight primary research from the past 3-5 years involving functional interrogation of alternative splicing in rodent and human liver, using both large-scale transcriptomic and focused mechanistic approaches. Because this is a rapidly advancing field, we anticipate that it will be transformative for the future of basic liver biology, as well as HCC diagnosis and management.

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“…HBC modifies alternative splicing of HLA-A by increasing intron five retention, and in contrast, HCV produces aberrant isoforms with lower levels of intron five retention. HBV-related hepatocellular carcinoma has elevated levels of HLA-A variants with intron five retention as compared to HCV-related cancers [ 51 ]. By modifying the levels of splice variants, tumour cells can evade an immune response [ 51 ].…”

Section: Virally-induced Alternative Splicing and Epigenetic Regulmentioning

confidence: 99%

“…HBV-related hepatocellular carcinoma has elevated levels of HLA-A variants with intron five retention as compared to HCV-related cancers [ 51 ]. By modifying the levels of splice variants, tumour cells can evade an immune response [ 51 ]. These results highlight the underlying molecular mechanisms utilised by HBV to promote carcinogenesis.…”

Section: Virally-induced Alternative Splicing and Epigenetic Regulmentioning

confidence: 99%

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Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

Francies

Dlamini

2021

Cells

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Global cancer incidence and mortality are on the rise. Although cancer is fundamentally a non-communicable disease, a large number of cancers are known to have a viral aetiology. A high burden of infectious agents (Human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B virus (HBV)) in certain Sub-Saharan African countries drives the rates of certain cancers. About one-third of all cancers in Africa are attributed to infection. Seven viruses have been identified with carcinogenic characteristics, namely the HPV, HBV, Hepatitis C virus (HCV), Epstein–Barr virus (EBV), Human T cell leukaemia virus 1 (HTLV-1), Kaposi’s Sarcoma Herpesvirus (KSHV), and HIV-1. The cellular splicing machinery is compromised upon infection, and the virus generates splicing variants that promote cell proliferation, suppress signalling pathways, inhibition of tumour suppressors, alter gene expression through epigenetic modification, and mechanisms to evade an immune response, promoting carcinogenesis. A number of these splice variants are specific to virally-induced cancers. Elucidating mechanisms underlying how the virus utilises these splice variants to maintain its latent and lytic phase will provide insights into novel targets for drug discovery. This review will focus on the splicing genomics, epigenetic modifications induced by and current therapeutic strategies against HPV, HBV, HCV, EBV, HTLV-1, KSHV and HIV-1.

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Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors

Cited by 15 publications

References 64 publications

Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors

Carbohydrate Sulfotransferase 4 Inhibits the Progression of Hepatitis B Virus-Related Hepatocellular Carcinoma and Is a Potential Prognostic Marker in Several Tumors

Alternative Splicing in Hepatocellular Carcinoma

Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

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