Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer

Overview

Journal Cancer Discov

Specialty Oncology

Date 2023 Apr 26

PMID 37098965

Authors

Ledong Wan

Kuan-Ting Lin

Mohammad Alinoor Rahman

Yuma Ishigami

Zhikai Wang

Mads A Jensen

John E Wilkinson

Youngkyu Park

David A Tuveson

Adrian R Krainer

Affiliations

Soon will be listed here.

Abstract

Significance: We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.

Citing Articles

DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells.

Leccese A, Ruta V, Panzeri V, Attili F, Spada C, Cianfanelli V Cancers (Basel). 2025; 17(4).

PMID: 40002164 PMC: 11852591. DOI: 10.3390/cancers17040570.

Targeting RNA splicing modulation: new perspectives for anticancer strategy?.

Lv X, Sun X, Gao Y, Song X, Hu X, Gong L J Exp Clin Cancer Res. 2025; 44(1):32.

PMID: 39885614 PMC: 11781073. DOI: 10.1186/s13046-025-03279-w.

Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8T and tumor cells.

Zhu G, Tang Z, Chu T, Wang B, Chen S, Tao C Signal Transduct Target Ther. 2025; 10(1):25.

PMID: 39837814 PMC: 11751439. DOI: 10.1038/s41392-024-02118-2.

Arginine demethylation of Serine/Arginine-rich splicing factor 1 enhances miRNA enrichment in small extracellular vesicles derived from pancreatic ductal adenocarcinoma cells.

Bhandari K, Kong J, Ho W, Bourne P, Mooers B, Ding W FASEB J. 2025; 39(1):e70287.

PMID: 39760222 PMC: 11827091. DOI: 10.1096/fj.202401811RR.

Pan-Cancer Analysis of PTBP1 to Identify it as a Prognostic and Immunological Biomarker.

Zhao Y, Wang Y, Xia Q, He H, Mao Q, Dong H Cancer Control. 2024; 31:10732748241302865.

PMID: 39612472 PMC: 11607764. DOI: 10.1177/10732748241302865.

References

Haward F, Maslon M, Yeyati P, Bellora N, Hansen J, Aitken S . Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function. Elife. 2021; 10. PMC: 8352595. DOI: 10.7554/eLife.65104. View

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Zhou Y, Han C, Wang E, Lorch A, Serafin V, Cho B . Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia. Cancer Discov. 2020; 10(9):1388-1409. PMC: 7483384. DOI: 10.1158/2159-8290.CD-19-1436. View

Lawson A, Abascal F, Coorens T, Hooks Y, ONeill L, Latimer C . Extensive heterogeneity in somatic mutation and selection in the human bladder. Science. 2020; 370(6512):75-82. DOI: 10.1126/science.aba8347. View

Hingorani S, Wang L, Multani A, Combs C, Deramaudt T, Hruban R . Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7(5):469-83. DOI: 10.1016/j.ccr.2005.04.023. View

Zhao Z, Chen C, Rillahan C, Shen R, Kitzing T, McNerney M . Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet. 2015; 47(5):539-43. PMC: 4414804. DOI: 10.1038/ng.3251. View

Xu X, Yang D, Ding J, Wang W, Chu P, Dalton N . ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell. 2005; 120(1):59-72. DOI: 10.1016/j.cell.2004.11.036. View

Rahman M, Krainer A, Abdel-Wahab O . SnapShot: Splicing Alterations in Cancer. Cell. 2020; 180(1):208-208.e1. PMC: 7291876. DOI: 10.1016/j.cell.2019.12.011. View

Kortlever R, Sodir N, Wilson C, Burkhart D, Pellegrinet L, Swigart L . Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell. 2017; 171(6):1301-1315.e14. PMC: 5720393. DOI: 10.1016/j.cell.2017.11.013. View

10.

Rahman M, Lin K, Bradley R, Abdel-Wahab O, Krainer A . Recurrent SRSF2 mutations in MDS affect both splicing and NMD. Genes Dev. 2020; 34(5-6):413-427. PMC: 7050488. DOI: 10.1101/gad.332270.119. View

11.

Gehrke N, Hovelmeyer N, Waisman A, Straub B, Weinmann-Menke J, Worns M . Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation. J Hepatol. 2018; 68(5):986-995. DOI: 10.1016/j.jhep.2018.01.008. View

12.

Weber A, Wasiliew P, Kracht M . Interleukin-1 (IL-1) pathway. Sci Signal. 2010; 3(105):cm1. DOI: 10.1126/scisignal.3105cm1. View

13.

Baralle F, Giudice J . Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017; 18(7):437-451. PMC: 6839889. DOI: 10.1038/nrm.2017.27. View

14.

Das S, Anczukow O, Akerman M, Krainer A . Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep. 2012; 1(2):110-7. PMC: 3334311. DOI: 10.1016/j.celrep.2011.12.001. View

15.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

16.

Yu T, Cazares O, Tang A, Kim H, Wald T, Verma A . SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal. Dev Cell. 2022; 57(5):624-637.e4. PMC: 8974236. DOI: 10.1016/j.devcel.2022.01.011. View

17.

Zheng X, Peng Q, Wang L, Zhang X, Huang L, Wang J . Serine/arginine-rich splicing factors: the bridge linking alternative splicing and cancer. Int J Biol Sci. 2020; 16(13):2442-2453. PMC: 7378643. DOI: 10.7150/ijbs.46751. View

18.

Biffi G, Oni T, Spielman B, Hao Y, Elyada E, Park Y . IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2018; 9(2):282-301. PMC: 6368881. DOI: 10.1158/2159-8290.CD-18-0710. View

19.

Karni R, de Stanchina E, Lowe S, Sinha R, Mu D, Krainer A . The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007; 14(3):185-93. PMC: 4595851. DOI: 10.1038/nsmb1209. View

20.

Anczukow O, Rosenberg A, Akerman M, Das S, Zhan L, Karni R . The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol. 2012; 19(2):220-8. PMC: 3272117. DOI: 10.1038/nsmb.2207. View