RNA splicing: a dual-edged sword for hepatocellular carcinoma

Kashyap, Anjali; Tripathi, Greesham; Tripathi, Avantika; Rao, Rashmi; Kashyap, Manju; Bhat, Anjali; Kumar, Deepak; Rajhans, Anjali; Kumar, Pravindra; Chandrashekar, Darshan S.; Mahmood, Riaz; Husain, Amjad; Zayed, Hatem; Bharti, Alok C.; Kashyap, Manoj Kumar

doi:10.1007/s12032-022-01726-8

Cited by 9 publications

(7 citation statements)

References 198 publications

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“…Chemotherapy clinical trials have shown that HBsAg-positive HCC patients had a lower survival benefit [ 32 , 41 ]. On the other hand, anti-apoptotic isoforms produced by RNA splicing may confer resistance to chemotherapy [ 42 ]. Our previous study has shown that CKLF1, variant 2 of the chemokine-like factor, and PCLAF tv1 contributed to doxorubicin resistance in HCC cells [ 17 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing

Liu

Wang

et al. 2023

IJMS

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Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Hepatitis B virus (HBV) infection accounts for nearly 50% of HCC cases. Recent studies indicate that HBV infection induces resistance to sorafenib, the first-line systemic treatment for advanced HCC for more than a decade, from 2007 to 2020. Our previous research shows that variant 1 (tv1) of proliferating cell nuclear antigen clamp-associated factor (PCLAF), overexpressed in HCC, protects against doxorubicin-induced apoptosis. However, there are no reports on the relevance of PCLAF in sorafenib resistance in HBV-related HCC. In this article, we found that PCLAF levels were higher in HBV-related HCC than in non-virus-related HCC using bioinformatics analysis. Immunohistochemistry (IHC) staining of clinical samples and the splicing reporter minigene assay using HCC cells revealed that PCLAF tv1 was elevated by HBV. Furthermore, HBV promoted the splicing of PCLAF tv1 by downregulating serine/arginine-rich splicing factor 2 (SRSF2), which hindered the inclusion of PCLAF exon 3 through a putative cis-element (116–123), “GATTCCTG”. The CCK-8 assay showed that HBV decreased cell susceptibility to sorafenib through SRSF2/PCLAF tv1. HBV reduced ferroptosis by decreasing intracellular Fe2+ levels and activating GPX4 expression via the SRSF2/PCLAF tv1 axis, according to a mechanism study. Suppressed ferroptosis, on the other hand, contributed to HBV-mediated sorafenib resistance through SRSF2/PCLAF tv1. These data suggested that HBV regulated PCLAF abnormal alternative splicing by suppressing SRSF2. HBV caused sorafenib resistance by reducing ferroptosis via the SRSF2/PCLAF tv1 axis. As a result, the SRSF2/PCLAF tv1 axis may be a prospective molecular therapeutic target in HBV-related HCC, as well as a predictor of sorafenib resistance. The inhibition of the SRSF2/PCLAF tv1 axis may be crucial in the emergence of systemic chemotherapy resistance in HBV-associated HCC.

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Section: Discussionmentioning

confidence: 99%

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing

Liu

Wang

et al. 2023

IJMS

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“…Imbalanced RNA splicing significantly threatens human health, often resulting in abnormal glucose metabolism, stroke, cardiovascular disease, and cancer ( 24 ). Targeting RNA shear factors is emerging as a potential antitumor therapeutic modality ( 25 – 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…This study revealed using bioinformatic analyses that TXNL4A can be used as a novel biomarker for prognosis and immune correlation in HCC. Considering TXNL4A is a gene in the RNA splicing pathway, TXNL4A is a promising novel target for RNA shear-targeting drugs or RNA vaccines ( 24 , 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Combined bulk RNA and single-cell RNA analyses reveal TXNL4A as a new biomarker for hepatocellular carcinoma

Zhu

Zhou

et al. 2023

Front. Oncol.

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IntroductionHepatocellular carcinoma (HCC) has a high mortality rate worldwide. The dysregulation of RNA splicing is a major event leading to the occurrence, progression, and drug resistance of cancer. Therefore, it is important to identify new biomarkers of HCC from the RNA splicing pathway.MethodsWe performed the differential expression and prognostic analyses of RNA splicing-related genes (RRGs) using The Cancer Genome Atlas-liver hepatocellular carcinoma (LIHC). The International Cancer Genome Consortium (ICGC)-LIHC dataset was used to construct and validate prognostic models, and the PubMed database was used to explore genes in the models to identify new markers. The screened genes were subjected to genomic analyses, including differential, prognostic, enrichment, and immunocorrelation analyses. Single-cell RNA (scRNA) data were used to further validate the immunogenetic relationship.ResultsOf 215 RRGs, we identified 75 differentially expressed prognosis-related genes, and a prognostic model incorporating thioredoxin like 4A (TXNL4A) was identified using least absolute shrinkage and selection operator regression analysis. ICGC-LIHC was used as a validation dataset to confirm the validity of the model. PubMed failed to retrieve HCC-related studies on TXNL4A. TXNL4A was highly expressed in most tumors and was associated with HCC survival. Chi-squared analyses indicated that TXNL4A expression positively correlated positively with the clinical features of HCC. Multivariate analyses revealed that high TXNL4A expression was an independent risk factor for HCC. Immunocorrelation and scRNA data analyses indicated that TXNL4A was correlated with CD8 T cell infiltration in HCC.ConclusionTherefore, we identified a prognostic and immune-related marker for HCC from the RNA splicing pathway.

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“…SF3B1 is the largest protein in the SF3b complex and has been regarded as a therapeutic target because of its frequent mutations in both hematologic cancers and solid tumors (10)(11)(12)(13). The high expression level of SF3B1 in hepatocellular carcinoma (HCC) has been correlated with increased tumor aggressiveness and shorter overall survival (OS) (14). SF3B1 is also upregulated in OSCC tissues (15).…”

Section: Spliceosome Complexmentioning

confidence: 99%

Emerging roles of alternative RNA splicing in oral squamous cell carcinoma

2022

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Alternative RNA splicing (ARS) is an essential and tightly regulated cellular process of post-transcriptional regulation of pre-mRNA. It produces multiple isoforms and may encode proteins with different or even opposite functions. The dysregulated ARS of pre-mRNA contributes to the development of many cancer types, including oral squamous cell carcinoma (OSCC), and may serve as a biomarker for the diagnosis and prognosis of OSCC and an attractive therapeutic target. ARS is mainly regulated by splicing factors, whose expression is also often dysregulated in OSCC and involved in tumorigenesis. This review focuses on the expression and roles of splicing factors in OSCC, the alternative RNA splicing events associated with OSCC, and recent advances in therapeutic approaches that target ARS.

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RNA splicing: a dual-edged sword for hepatocellular carcinoma

Cited by 9 publications

References 198 publications

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing

HBV Enhances Sorafenib Resistance in Hepatocellular Carcinoma by Reducing Ferroptosis via SRSF2-Mediated Abnormal PCLAF Splicing

Combined bulk RNA and single-cell RNA analyses reveal TXNL4A as a new biomarker for hepatocellular carcinoma

Emerging roles of alternative RNA splicing in oral squamous cell carcinoma

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