Research progress of alternative splicing in pancreatic cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HE Chao ¹ , ZENG Yunqiu ¹ , ZOU Bin ¹ , HUANG Shaobin ¹ , BAI Jian ¹ ,  LUO Shuntian ²

1. Department of General Surgery, Changsha Central Hospital, University of South China, Changsha 410018, P. R. China;
2. Department of General Surgery, Zhongshan Chenxinghai Hospital, Zhongshan, Guangdong 528415, P. R. China;

Corresponding author：

LUO Shuntian, Email: 2236303745@qq.com

Keywords：

Pancreatic cancer; alternative splicing; carcinogenesis; tumor progression; chemoresistance

DOI：

10.7507/1007-9424.202105016

Video：

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Objective To summarize the research progress of alternative splicing in pancreatic cancer, and to provide reference for further research. Method The experimental and clinical studies of alternative splicing in pancreatic cancer were reviewed.Results Alternative splicing dysregulation resulted in changed gene expression or novel isoform formation, thereby influencing the carcinogenesis, progression or chemoresistance of pancreatic cancer. The differentially expressed alternative splicing isoforms may serve as diagnostic markers, indicators of aggressiveness or prognostic markers of pancreatic cancer. Conclusion Further investigation of the molecular mechanisms of alternative splicing in carcinogenesis and progression of pancreatic cancer is a new way to improve the early diagnosis and treatment of pancreatic cancer.

Citation： HE Chao, ZENG Yunqiu, ZOU Bin, HUANG Shaobin, BAI Jian, LUO Shuntian. Research progress of alternative splicing in pancreatic cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(3): 415-420. doi: 10.7507/1007-9424.202105016 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Luo G, Fan Z, Gong Y, et al. Characteristics and Outcomes of Pancreatic Cancer by Histological Subtypes. Pancreas, 2019, 48(6): 817-822.
3.	柯能文, 刘续宝. 胰腺癌外科治疗华西 10 年经验. 中国普外基础与临床杂志, 2021, 28(1): 4-7.
4.	Bonnal SC, López-Oreja I, Valcárcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol, 2020, 17(8): 457-474.
5.	王一晨, 王瑾, 杨文山, 等. 胃癌基因芯片测序与异常基因差异表达. 中国普外基础与临床杂志, 2020, 27(7): 790-800.
6.	Xu L, Pan J, Ding Y, et al. Survival-associated alternative splicing events and prognostic signatures in pancreatic cancer. Front Genet, 2020, 11: 522383. doi: 10.3389/fgene.2020.522383.
7.	Qiao L, Xie N, Bai Y, et al. Identification of upregulated HNRNPs associated with poor prognosis in pancreatic cancer. Biomed Res Int, 2019, 2019: 5134050. doi: 10.1155/2019/5134050.
8.	Sampath J, Long PR, Shepard RL, et al. Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells. Am J Pathol, 2003, 163(5): 1781-1790.
9.	Xiao W, Chen X, Li X, et al. RBM10 regulates human TERT gene splicing and inhibits pancreatic cancer progression. Am J Cancer Res, 2021, 11(1): 157-170.
10.	Ueda J, Matsuda Y, Yamahatsu K, et al. Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene, 2014, 33(36): 4485-4495.
11.	Calabretta S, Bielli P, Passacantilli I, et al. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. Oncogene, 2016, 35(16): 2031-2039.
12.	Chen S, Yang C, Wang ZW, et al. CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. J Hematol Oncol, 2021, 14(1): 60. doi:10.1186/s13045-021-01072-8.
13.	Jiang P, Li Z, Tian F, et al. Fyn/heterogeneous nuclear ribonucleoprotein E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin β1. Int J Oncol, 2017, 51(1): 169-183.
14.	Li M, Wu P, Yang Z, et al. miR-193a-5p promotes pancreatic cancer cell metastasis through SRSF6-mediated alternative splicing of OGDHL and ECM1. Am J Cancer Res, 2020, 10(1): 38-59.
15.	Meng LD, Shi GD, Ge WL, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. Cancer Lett, 2020, 494: 107-120.
16.	Abetamann V, Kern HF, Elsässer HP. Differential expression of the hyaluronan receptors CD44 and RHAMM in human pancreatic cancer cells. Clin Cancer Res, 1996, 2(9): 1607-1618.
17.	Preca BT, Bajdak K, Mock K, et al. A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer, 2015, 137(11): 2566-2577.
18.	Melchionna R, Iapicca P, Di Modugno F, et al. The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome. Oncoimmunology, 2016, 5(12): e1221556. doi: 10.1080/2162402X.2016.
19.	Simon B, Bartsch D, Barth P, et al. Frequent abnormalities of the putative tumor suppressor gene FHIT at 3p14. 2 in pancreatic carcinoma cell lines. Cancer Res, 1998, 58(8): 1583-1587.
20.	Ding WQ, Cheng ZJ, McElhiney J, et al. Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma. Cancer Res, 2002, 62(18): 5223-5229.
21.	Chakedis J, French R, Babicky M, et al. Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. Oncotarget, 2016, 7(29): 45959-45975.
22.	Chakedis J, French R, Babicky M, et al. A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene, 2016, 35(25): 3249-3259.
23.	Guo Q, Quan M, Dong J, et al. The WW domains dictate isoform-specific regulation of YAP1 stability and pancreatic cancer cell malignancy. Theranostics, 2020, 10(10): 4422-4436.
24.	Ramchandani D, Unruh D, Lewis CS, et al. Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions. Lab Invest, 2016, 96(12): 1234-1245.
25.	Unruh D, Turner K, Srinivasan R, et al. Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. Int J Cancer, 2014, 134(1): 9-20.
26.	Unruh D, Ünlü B, Lewis CS, et al. Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma. Oncotarget, 2016, 7(18): 25264-25275.
27.	Signaevsky M, Hobbs J, Doll J, et al. Role of alternatively spliced tissue factor in pancreatic cancer growth and angiogenesis. Semin Thromb Hemost, 2008, 34(2): 161-169.
28.	Vickers SM, Huang ZQ, MacMillan-Crow L, et al. Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy. J Gastrointest Surg, 2002, 6(4): 546-553.
29.	Wei D, Wang L, Kanai M, et al. KLF4α up-regulation promotes cell cycle progression and reduces survival time of patients with pancreatic cancer. Gastroenterology, 2010, 139(6): 2135-2145.
30.	Jahan R, Macha MA, Rachagani S, et al. Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-β1/FAK/ERK pathway. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(8): 2538-2549.
31.	Zhu Y, Zhang JJ, Xie KL, et al. Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy-related positive feedback loops signaling. J Transl Med, 2014, 12: 309. doi: 10.1186/s12967-014-0309-8.
32.	Nie H, Huang PQ, Jiang SH, et al. The short isoform of PRLR suppresses the pentose phosphate pathway and nucleotide synthesis through the NEK9-Hippo axis in pancreatic cancer. Theranostics, 2021, 11(8): 3898-3915.
33.	Choi S, Wang D, Chen X, et al. Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression. Mol Cancer, 2019, 18(1): 92. doi: 10.1186/s12943-019-1018-y.
34.	Hagiwara K, Harimoto N, Yokobori T, et al. High co-expression of large tenascin C Splice variants in stromal tissue and annexin A2 in cancer cell membranes is associated with poor prognosis in pancreatic cancer. Ann Surg Oncol, 2020, 27(3): 924-930.
35.	Gong XG, Lv YF, Li XQ, et al. Gemcitabine resistance induced by interaction between alternatively spliced segment of tenascin-C and annexin A2 in pancreatic cancer cells. Biol Pharm Bull, 2010, 33(8): 1261-1267.
36.	Archange C, Nowak J, Garcia S, et al. The WSB1 gene is involved in pancreatic cancer progression. PLoS One, 2008, 3(6): e2475. doi: 10.1371/journal.pone.0002475.
37.	Carrière C, Mirocha S, Deharvengt S, et al. Aberrant expressions of AP-2α splice variants in pancreatic cancer. Pancreas, 2011, 40(5): 695-700.
38.	Xu Q, Gao J, Li Z. Identification of a novel alternative splicing transcript variant of the suppressor of fused: Relationship with lymph node metastasis in pancreatic ductal adenocarcinoma. Int J Oncol, 2016, 49(6): 2611-2619.
39.	Unruh D, Sagin F, Adam M, et al. Levels of alternatively spliced tissue factor in the plasma of patients with pancreatic cancer may help predict aggressive tumor phenotype. Ann Surg Oncol, 2015, 22 Suppl 3: S1206-S1211.
40.	Ding WQ, Kuntz SM, Miller LJ. A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron. Cancer Res, 2002, 62(3): 947-952.
41.	Arafat H, Lazar M, Salem K, et al. Tumor-specific expression and alternative splicing of the COL6A3 gene in pancreatic cancer. Surgery, 2011, 150(2): 306-315.
42.	Choudhury A, Moniaux N, Ringel J, et al. Alternate splicing at the 3′ -end of the human pancreatic tumor-associated mucin MUC4 cDNA. Teratog Carcinog Mutagen, 2001, 21(1): 83-96.
43.	Wu CL, Chao YJ, Yang TM, et al. Dual role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor prognosis in early cancer and CD44ν is an indicator for recurrence in advanced cancer. BMC Cancer, 2015, 15: 903. doi: 10.1186/s12885-015-1924-3.
44.	Hartel M, Narla G, Wente MN, et al. Increased alternative splicing of the KLF6 tumour suppressor gene correlates with prognosis and tumour grade in patients with pancreatic cancer. Eur J Cancer, 2008, 44(13): 1895-1903.
45.	王方华, 吴怡林, 龚建平. KRAS 突变与胰腺癌的发生及治疗的研究进展. 中国普外基础与临床杂志, 2019, 26(6): 764-768.
46.	Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med, 2018, 24(4): 497-504.

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Luo G, Fan Z, Gong Y, et al. Characteristics and Outcomes of Pancreatic Cancer by Histological Subtypes. Pancreas, 2019, 48(6): 817-822.
3. 柯能文, 刘续宝. 胰腺癌外科治疗华西 10 年经验. 中国普外基础与临床杂志, 2021, 28(1): 4-7.
4. Bonnal SC, López-Oreja I, Valcárcel J. Roles and mechanisms of alternative splicing in cancer - implications for care. Nat Rev Clin Oncol, 2020, 17(8): 457-474.
5. 王一晨, 王瑾, 杨文山, 等. 胃癌基因芯片测序与异常基因差异表达. 中国普外基础与临床杂志, 2020, 27(7): 790-800.
6. Xu L, Pan J, Ding Y, et al. Survival-associated alternative splicing events and prognostic signatures in pancreatic cancer. Front Genet, 2020, 11: 522383. doi: 10.3389/fgene.2020.522383.
7. Qiao L, Xie N, Bai Y, et al. Identification of upregulated HNRNPs associated with poor prognosis in pancreatic cancer. Biomed Res Int, 2019, 2019: 5134050. doi: 10.1155/2019/5134050.
8. Sampath J, Long PR, Shepard RL, et al. Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells. Am J Pathol, 2003, 163(5): 1781-1790.
9. Xiao W, Chen X, Li X, et al. RBM10 regulates human TERT gene splicing and inhibits pancreatic cancer progression. Am J Cancer Res, 2021, 11(1): 157-170.
10. Ueda J, Matsuda Y, Yamahatsu K, et al. Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene, 2014, 33(36): 4485-4495.
11. Calabretta S, Bielli P, Passacantilli I, et al. Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells. Oncogene, 2016, 35(16): 2031-2039.
12. Chen S, Yang C, Wang ZW, et al. CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. J Hematol Oncol, 2021, 14(1): 60. doi:10.1186/s13045-021-01072-8.
13. Jiang P, Li Z, Tian F, et al. Fyn/heterogeneous nuclear ribonucleoprotein E1 signaling regulates pancreatic cancer metastasis by affecting the alternative splicing of integrin β1. Int J Oncol, 2017, 51(1): 169-183.
14. Li M, Wu P, Yang Z, et al. miR-193a-5p promotes pancreatic cancer cell metastasis through SRSF6-mediated alternative splicing of OGDHL and ECM1. Am J Cancer Res, 2020, 10(1): 38-59.
15. Meng LD, Shi GD, Ge WL, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. Cancer Lett, 2020, 494: 107-120.
16. Abetamann V, Kern HF, Elsässer HP. Differential expression of the hyaluronan receptors CD44 and RHAMM in human pancreatic cancer cells. Clin Cancer Res, 1996, 2(9): 1607-1618.
17. Preca BT, Bajdak K, Mock K, et al. A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer, 2015, 137(11): 2566-2577.
18. Melchionna R, Iapicca P, Di Modugno F, et al. The pattern of hMENA isoforms is regulated by TGF-β1 in pancreatic cancer and may predict patient outcome. Oncoimmunology, 2016, 5(12): e1221556. doi: 10.1080/2162402X.2016.
19. Simon B, Bartsch D, Barth P, et al. Frequent abnormalities of the putative tumor suppressor gene FHIT at 3p14. 2 in pancreatic carcinoma cell lines. Cancer Res, 1998, 58(8): 1583-1587.
20. Ding WQ, Cheng ZJ, McElhiney J, et al. Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma. Cancer Res, 2002, 62(18): 5223-5229.
21. Chakedis J, French R, Babicky M, et al. Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. Oncotarget, 2016, 7(29): 45959-45975.
22. Chakedis J, French R, Babicky M, et al. A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene, 2016, 35(25): 3249-3259.
23. Guo Q, Quan M, Dong J, et al. The WW domains dictate isoform-specific regulation of YAP1 stability and pancreatic cancer cell malignancy. Theranostics, 2020, 10(10): 4422-4436.
24. Ramchandani D, Unruh D, Lewis CS, et al. Activation of carbonic anhydrase IX by alternatively spliced tissue factor under late-stage tumor conditions. Lab Invest, 2016, 96(12): 1234-1245.
25. Unruh D, Turner K, Srinivasan R, et al. Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. Int J Cancer, 2014, 134(1): 9-20.
26. Unruh D, Ünlü B, Lewis CS, et al. Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma. Oncotarget, 2016, 7(18): 25264-25275.
27. Signaevsky M, Hobbs J, Doll J, et al. Role of alternatively spliced tissue factor in pancreatic cancer growth and angiogenesis. Semin Thromb Hemost, 2008, 34(2): 161-169.
28. Vickers SM, Huang ZQ, MacMillan-Crow L, et al. Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy. J Gastrointest Surg, 2002, 6(4): 546-553.
29. Wei D, Wang L, Kanai M, et al. KLF4α up-regulation promotes cell cycle progression and reduces survival time of patients with pancreatic cancer. Gastroenterology, 2010, 139(6): 2135-2145.
30. Jahan R, Macha MA, Rachagani S, et al. Axed MUC4 (MUC4/X) aggravates pancreatic malignant phenotype by activating integrin-β1/FAK/ERK pathway. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(8): 2538-2549.
31. Zhu Y, Zhang JJ, Xie KL, et al. Specific-detection of clinical samples, systematic functional investigations, and transcriptome analysis reveals that splice variant MUC4/Y contributes to the malignant progression of pancreatic cancer by triggering malignancy-related positive feedback loops signaling. J Transl Med, 2014, 12: 309. doi: 10.1186/s12967-014-0309-8.
32. Nie H, Huang PQ, Jiang SH, et al. The short isoform of PRLR suppresses the pentose phosphate pathway and nucleotide synthesis through the NEK9-Hippo axis in pancreatic cancer. Theranostics, 2021, 11(8): 3898-3915.
33. Choi S, Wang D, Chen X, et al. Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression. Mol Cancer, 2019, 18(1): 92. doi: 10.1186/s12943-019-1018-y.
34. Hagiwara K, Harimoto N, Yokobori T, et al. High co-expression of large tenascin C Splice variants in stromal tissue and annexin A2 in cancer cell membranes is associated with poor prognosis in pancreatic cancer. Ann Surg Oncol, 2020, 27(3): 924-930.
35. Gong XG, Lv YF, Li XQ, et al. Gemcitabine resistance induced by interaction between alternatively spliced segment of tenascin-C and annexin A2 in pancreatic cancer cells. Biol Pharm Bull, 2010, 33(8): 1261-1267.
36. Archange C, Nowak J, Garcia S, et al. The WSB1 gene is involved in pancreatic cancer progression. PLoS One, 2008, 3(6): e2475. doi: 10.1371/journal.pone.0002475.
37. Carrière C, Mirocha S, Deharvengt S, et al. Aberrant expressions of AP-2α splice variants in pancreatic cancer. Pancreas, 2011, 40(5): 695-700.
38. Xu Q, Gao J, Li Z. Identification of a novel alternative splicing transcript variant of the suppressor of fused: Relationship with lymph node metastasis in pancreatic ductal adenocarcinoma. Int J Oncol, 2016, 49(6): 2611-2619.
39. Unruh D, Sagin F, Adam M, et al. Levels of alternatively spliced tissue factor in the plasma of patients with pancreatic cancer may help predict aggressive tumor phenotype. Ann Surg Oncol, 2015, 22 Suppl 3: S1206-S1211.
40. Ding WQ, Kuntz SM, Miller LJ. A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: role of reduced sellular U2AF35 and a suboptimal 3'-splicing site leading to retention of the fourth intron. Cancer Res, 2002, 62(3): 947-952.
41. Arafat H, Lazar M, Salem K, et al. Tumor-specific expression and alternative splicing of the COL6A3 gene in pancreatic cancer. Surgery, 2011, 150(2): 306-315.
42. Choudhury A, Moniaux N, Ringel J, et al. Alternate splicing at the 3′ -end of the human pancreatic tumor-associated mucin MUC4 cDNA. Teratog Carcinog Mutagen, 2001, 21(1): 83-96.
43. Wu CL, Chao YJ, Yang TM, et al. Dual role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor prognosis in early cancer and CD44ν is an indicator for recurrence in advanced cancer. BMC Cancer, 2015, 15: 903. doi: 10.1186/s12885-015-1924-3.
44. Hartel M, Narla G, Wente MN, et al. Increased alternative splicing of the KLF6 tumour suppressor gene correlates with prognosis and tumour grade in patients with pancreatic cancer. Eur J Cancer, 2008, 44(13): 1895-1903.
45. 王方华, 吴怡林, 龚建平. KRAS 突变与胰腺癌的发生及治疗的研究进展. 中国普外基础与临床杂志, 2019, 26(6): 764-768.
46. Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med, 2018, 24(4): 497-504.

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