Epithelial splicing regulatory protein 2–mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis

Hyun, Jeongeun; Sun, Zhaoli; Ahmadi, Ali; Bangru, Sushant; Chembazhi, Ullas Valiya; Du, Kuo; Chen, Tianyi; Tsukamoto, Hidekazu; Rusyn, Ivan; Kalsotra, Auinash

doi:10.1172/jci132691

Cited by 54 publications

(72 citation statements)

References 75 publications

(102 reference statements)

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“…This has not been reported to date in vivo, but it would be of interest to examine because ESRP2 is able to support cell-cell adhesion and attenuate the motility of cancer cells in vitro. 85 Esrp2 is an important stress response factor that changes dynamically during liver injury and recovery, and it is involved in adult-to-fetal reversion in injured hepatocytes 53 (Figure 1). Livers from Esrp2 -/mice were marked by the presence of small immature hepatocytes that produced less albumin and showed evidence of hyperproliferation.…”

Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

“… 49 , 50 , 51 Recent studies have shown significant alternative splicing changes during normal fetal-to-adult liver maturation 52 and during injury-associated adult-to-fetal reversion in hepatocytes. 53 Analyses of alternative splicing events in mouse liver just before birth, shortly after birth, and in adulthood found that the most dramatic splicing changes (affecting >500 genes) occurred at the switch between the prenatal and postnatal periods, and that many of these genes encoded cytoskeleton and chromatin modification regulators. 52 Furthermore, comparison of different cell types between P0 and adult mouse showed that more than 50% of postnatal splicing transitions in the liver occurred specifically within hepatocytes.…”

Section: Alternative Splicing In Liver Development and Maturationmentioning

confidence: 99%

“…Esrp2 is an important stress response factor that changes dynamically during liver injury and recovery, and it is involved in adult-to-fetal reversion in injured hepatocytes 53 ( Figure 1 ). Livers from Esrp2 -/- mice were marked by the presence of small immature hepatocytes that produced less albumin and showed evidence of hyperproliferation.…”

Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

“… 87 Recent work has extended on the findings in Esrp2 -/- mice to provide evidence for ESRP2 function in human alcoholic liver injury. 53 Hyun et al 53 showed that ESRP2 is down-regulated significantly in severe human liver injury associated with alcoholic hepatitis, potentially via transcriptional down-regulation by the inflammatory cytokines tumor necrosis factor α and interleukin 1β ( Figure 1 ). In addition to reduced overall expression, ESRP2 protein was mislocalized to the cytoplasm in liver tissue from alcoholic hepatitis patients.…”

Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

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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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Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

Section: Alternative Splicing In Liver Development and Maturationmentioning

confidence: 99%

Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

Section: Epithelial Splicing Regulatory Protein 2 Splicing Factor Regmentioning

confidence: 99%

See 2 more Smart Citations

Alternative Splicing in Hepatocellular Carcinoma

Lee

Alcedo

Kim

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…In fact, the scRNA-seq studies reveal several distinct hepatocyte subpopulations in the normal liver, which have been attributed to liver zonation and differences in oxygen and nutrient supply. 10,11 Further studies are required to determine whether these scRNA-seq defined hepatocyte subpopulations differentially respond to repair signals in response to injury 12 and if new hepatocyte subpopulations with higher proliferation capacity give rise to hepatocellular carcinoma.…”

mentioning

confidence: 99%

Equal opportunity offer for all hepatocytes

Dai

Ott

Sharma

2020

Journal of Hepatology

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Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression

Yan,

Fang,

Liu

et al. 2023

Advanced Science

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Tumors usually display fetal‐like characteristics, and many oncofetal proteins have been identified. However, fetal‐like reprogramming of RNA splicing in hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with tumor progression. By combining RNA‐Seq with splicing analysis, it is identified that ESRP2 controls the fetal‐to‐adult switch of multiple splice isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12 protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1 kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint therapy achieved potent tumor regression in mice. Overall, the findings reveal a previously unexplored onco‐fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC.

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Epithelial splicing regulatory protein 2–mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis

Cited by 54 publications

References 75 publications

Alternative Splicing in Hepatocellular Carcinoma

Alternative Splicing in Hepatocellular Carcinoma

Equal opportunity offer for all hepatocytes

Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression

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