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B7-H3 is spliced by SRSF3 in colorectal cancer

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Abstract

B7-H3, an important co-inhibitor, is abnormally highly expressed in a variety of malignancies. The antibodies targeting B7-H3 have exhibited beneficial therapeutic effects in clinical trials. Therefore, discovery of the regulatory factors in B7-H3 expression may provide new strategies for tumor therapy. Here, we investigated the splicing factors involved in the splicing of B7-H3. By individual knockdown of the splicing factors in colorectal cancer (CRC) cells, we found that B7-H3 expression was markedly inhibited by SRSF3 and SRSF8, especially SRSF3. Then we found that both SRSF3 and B7-H3 were highly expressed in CRC tissues. Moreover, high-expression of either SRSF3 or B7-H3 was significantly correlated with poor prognosis of patients. The expression of B7-H3 mRNA and protein were evidently reduced by SRSF3 silence, but were enhanced by overexpression of SRSF3 in both HCT-116 and HCT-8 cells. The results from the RNA immunoprecipitation (RIP) assays demonstrated that SRSF3 protein directly binds to B7-H3 mRNA. In addition, we constructed a minigene recombinant plasmid for expressing B7-H3 exons 3–6. We found that SRSF3 contributed to the retention of B7-H3 exon 4. These findings demonstrate that SRSF3 involves in the splicing of B7-H3 by directly binding to its exon 4 and/or 6. It may provide novel insights into the regulatory mechanisms of B7-H3 expression and potential strategies for the treatment of CRC.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  Google Scholar 

  2. Gessani S, Belardelli F (2019) Immune dysfunctions and immunotherapy in colorectal cancer: the role of dendritic cells. Cancers. https://doi.org/10.3390/cancers11101491

    Article  PubMed  PubMed Central  Google Scholar 

  3. Thanikachalam K, Khan G (2019) Colorectal cancer and nutrition. Nutrients. https://doi.org/10.3390/nu11010164

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bailey CE, Hu CY, You YN, Bednarski BK, Rodriguez-Bigas MA, Skibber JM, Cantor SB, Chang GJ (2015) Increasing disparities in the age-related incidences of colon and rectal cancers in the United States, 1975–2010. JAMA Surg 150:17–22. https://doi.org/10.1001/jamasurg.2014.1756

    Article  PubMed  PubMed Central  Google Scholar 

  5. Messersmith WA (2019) NCCN guidelines updates: management of metastatic colorectal cancer. J Natl Comprehensive Cancer Netw 17:599–601. https://doi.org/10.6004/jnccn.2019.5014

    Article  Google Scholar 

  6. Spartalis C, Schmidt EM, Elmasry M, Schulz GB, Kirchner T, Horst D (2019) In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer. Cancer Sci 110:2529–2539. https://doi.org/10.1111/cas.14077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Torring ML, Falborg AZ, Jensen H, Neal RD, Weller D, Reguilon I, Menon U, Vedsted P (2019) Advanced-stage cancer and time to diagnosis: an international cancer benchmarking partnership (ICBP) cross-sectional study. Eur J Cancer Care 28:e13100. https://doi.org/10.1111/ecc.13100

    Article  Google Scholar 

  8. Jiao Q, Ren Y, Ariston Gabrie AN, Wang Q, Wang Y, Du L, Liu X, Wang C, Wang YS (2020) Advances of immune checkpoints in colorectal cancer treatment. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 123:109745. https://doi.org/10.1016/j.biopha.2019.109745

    Article  CAS  Google Scholar 

  9. Janakiram M, Shah UA, Liu W, Zhao A, Schoenberg MP, Zang X (2017) The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7–H3. Immunol Rev 276:26–39. https://doi.org/10.1111/imr.12521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pollizzi KN, Powell JD (2014) Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 14:435–446. https://doi.org/10.1038/nri3701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Driessens G, Kline J, Gajewski TF (2009) Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol Rev 229:126–44. https://doi.org/10.1111/j.1600-065X.2009.00771.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Seliger B, Quandt D (2012) The expression, function, and clinical relevance of B7 family members in cancer. Cancer Immunol Immunother 61:1327–1341. https://doi.org/10.1007/s00262-012-1293-6

    Article  CAS  PubMed  Google Scholar 

  13. Chen L, Flies DB (2013) Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 13:227–242. https://doi.org/10.1038/nri3405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Picarda E, Ohaegbulam KC, Zang X (2016) Molecular pathways: targeting B7–H3 (CD276) for human cancer immunotherapy. Clin Cancer Res 22:3425–3431. https://doi.org/10.1158/1078-0432.Ccr-15-2428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chapoval AI, Ni J, Lau JS et al (2001) B7–H3: a co stimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2:269–274. https://doi.org/10.1038/85339

    Article  CAS  PubMed  Google Scholar 

  16. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang T, Wang F, Wu JY et al (2018) Clinical correlation of B7–H3 and B3GALT4 with the prognosis of colorectal cancer. World J Gastroenterol 24:3538–3546. https://doi.org/10.3748/wjg.v24.i31.3538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jiang B, Zhang T, Liu F, Sun Z, Shi H, Hua D, Yang C (2016) The co-stimulatory molecule B7–H3 promotes the epithelial-mesenchymal transition in colorectal cancer. Oncotarget 7:31755–31771. https://doi.org/10.18632/oncotarget.9035

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, Scardino PT, Sharma P, Allison JP (2007) B7–H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 104:19458–19463. https://doi.org/10.1073/pnas.0709802104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li G, Quan Y, Che F, Wang L (2018) B7–H3 in tumors: friend or foe for tumor immunity? Cancer Chemother Pharmacol 81:245–253. https://doi.org/10.1007/s00280-017-3508-1

    Article  CAS  PubMed  Google Scholar 

  21. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–463. https://doi.org/10.1038/nature08909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476. https://doi.org/10.1038/nature07509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Song X, Wan X, Huang T et al (2019) SRSF3-regulated RNA alternative splicing promotes glioblastoma tumorigenicity by affecting multiple cellular processes. Can Res 79:5288–5301. https://doi.org/10.1158/0008-5472.Can-19-1504

    Article  CAS  Google Scholar 

  24. Lee Y, Rio DC (2015) Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 84:291–323. https://doi.org/10.1146/annurev-biochem-060614-034316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. He C, Zhou F, Zuo Z, Cheng H, Zhou R (2009) A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis. PLoS ONE 4:e4732. https://doi.org/10.1371/journal.pone.0004732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang J, Manley JL (2013) Misregulation of pre-mRNA alternative splicing in cancer. Cancer Discov 3:1228–1237. https://doi.org/10.1158/2159-8290.Cd-13-0253

    Article  CAS  PubMed  Google Scholar 

  27. Koedoot E, Wolters L, van de Water B, Devedec SEL (2019) Splicing regulatory factors in breast cancer hallmarks and disease progression. Oncotarget 10:6021–6037. https://doi.org/10.18632/oncotarget.27215

    Article  PubMed  Google Scholar 

  28. Chen J, Weiss WA (2015) Alternative splicing in cancer: implications for biology and therapy. Oncogene 34:1–14. https://doi.org/10.1038/onc.2013.570

    Article  CAS  PubMed  Google Scholar 

  29. Cohen-Eliav M, Golan-Gerstl R, Siegfried Z, Andersen CL, Thorsen K, Orntoft TF, Mu D, Karni R (2013) The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers. J Pathol 229:630–639. https://doi.org/10.1002/path.4129

    Article  CAS  PubMed  Google Scholar 

  30. Das S, Anczukow O, Akerman M, Krainer AR (2012) Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep 1:110–117. https://doi.org/10.1016/j.celrep.2011.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Park WC, Kim HR, Kang DB et al (2016) Comparative expression patterns and diagnostic efficacies of SR splicing factors and HNRNPA1 in gastric and colorectal cancer. BMC Cancer 16:358. https://doi.org/10.1186/s12885-016-2387-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shi X, Zhang Y, Cao B et al (2013) Genes involved in the transition from normal epithelium to intraepithelial neoplasia are associated with colorectal cancer patient survival. Biochem Biophys Res Commun 435:282–288. https://doi.org/10.1016/j.bbrc.2013.04.063

    Article  CAS  PubMed  Google Scholar 

  33. Tsukamoto S, Ishikawa T, Iida S, Ishiguro M, Mogushi K, Mizushima H, Uetake H, Tanaka H, Sugihara K (2011) Clinical significance of osteoprotegerin expression in human colorectal cancer. Clin Cancer Res 17:2444–2450. https://doi.org/10.1158/1078-0432.CCR-10-2884

    Article  CAS  PubMed  Google Scholar 

  34. Khamas A, Ishikawa T, Shimokawa K et al (2012) Screening for epigenetically masked genes in colorectal cancer Using 5-Aza-2'-deoxycytidine, microarray and gene expression profile. Cancer Genomics Proteomics 9:67–75

    CAS  PubMed  Google Scholar 

  35. Kurokawa K, Akaike Y, Masuda K, Kuwano Y, Nishida K, Yamagishi N, Kajita K, Tanahashi T, Rokutan K (2014) Downregulation of serine/arginine-rich splicing factor 3 induces G1 cell cycle arrest and apoptosis in colon cancer cells. Oncogene 33:1407–1417. https://doi.org/10.1038/onc.2013.86

    Article  CAS  PubMed  Google Scholar 

  36. Wang H, Zhang CZ, Lu SX et al (2019) A coiled-coil domain containing 50 splice variant is modulated by serine/arginine-rich splicing factor 3 and promotes hepatocellular carcinoma in mice by the Ras signaling pathway. Hepatology 69:179–195. https://doi.org/10.1002/hep.30147

    Article  CAS  PubMed  Google Scholar 

  37. Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, Diaz LA Jr (2019) Immunotherapy in colorectal cancer: rationale, challenges and potential. Nature reviews. Gastroenterol Hepatol 16:361–375. https://doi.org/10.1038/s41575-019-0126-x

    Article  Google Scholar 

  38. Kreidieh M, Mukherji D, Temraz S, Shamseddine A (2020) Expanding the scope of immunotherapy in colorectal cancer: current clinical approaches and future directions. BioMed Res Int 2020:9037217. https://doi.org/10.1155/2020/9037217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Emambux S, Tachon G, Junca A, Tougeron D (2018) Results and challenges of immune checkpoint inhibitors in colorectal cancer. Expert Opin Biol Ther 18:561–573. https://doi.org/10.1080/14712598.2018.1445222

    Article  CAS  PubMed  Google Scholar 

  40. Zhao J, Meng Z, Xie C et al (2019) B7–H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma. Int J Biochem Cell Biol 108:84–91. https://doi.org/10.1016/j.biocel.2019.01.011

    Article  CAS  PubMed  Google Scholar 

  41. Zhang P, Yu S, Li H et al (2015) ILT4 drives B7–H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer. FEBS Lett 589:2248–2256. https://doi.org/10.1016/j.febslet.2015.06.037

    Article  CAS  PubMed  Google Scholar 

  42. Purvis IJ, Avilala J, Guda MR, Venkataraman S, Vibhakar R, Tsung AJ, Velpula KK, Asuthkar S (2019) Role of MYC-miR-29-B7-H3 in medulloblastoma growth and angiogenesis. J Clin Med. https://doi.org/10.3390/jcm8081158

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhou X, Mao Y, Zhu J et al (2016) TGF-beta1 promotes colorectal cancer immune escape by elevating B7–H3 and B7–H4 via the miR-155/miR-143 axis. Oncotarget 7:67196–67211. https://doi.org/10.18632/oncotarget.11950

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chen C, Zhu YB, Qu QX, Ge Y, Huang JA, Wang Y, Zhang XG (2009) CD40-activated apoptotic tumor cell-pulsed dendritic cell could potentially elicit antitumor immune response: involvement of up-regulation of B7–H3 expression. J Immunother 32:29–35. https://doi.org/10.1097/CJI.0b013e31818c8816

  45. Inamura K, Amori G, Yuasa T, Yamamoto S, Yonese J, Ishikawa Y (2019) Relationship of B7–H3 expression in tumor cells and tumor vasculature with FOXP3+ regulatory T cells in renal cell carcinoma. Cancer Manag Res 11:7021–7030. https://doi.org/10.2147/CMAR.S209205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lina TT, Gonzalez J, Pinchuk IV, Beswick EJ, Reyes VE (2019) Helicobacter pylori elicits B7H3 expression on gastric epithelial cells: implications in local T cell regulation and subset development during infection. Clin Oncol Res. https://doi.org/10.31487/j.cor.2019.05.05

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kuranaga Y, Sugito N, Shinohara H, Tsujino T, Taniguchi K, Komura K, Ito Y, Soga T, Akao Y (2018) SRSF3, a splicer of the PKM gene, regulates cell growth and maintenance of cancer-specific energy metabolism in colon cancer cells. Int J Mol Sci. https://doi.org/10.3390/ijms19103012

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lin JC, Lee YC, Tan TH, Liang YC, Chuang HC, Fann YC, Johnson KR, Lin YJ (2018) RBM4-SRSF3-MAP4K4 splicing cascade modulates the metastatic signature of colorectal cancer cell. Biochimica et biophysica acta. Mol Cell Res 1865:259–272. https://doi.org/10.1016/j.bbamcr.2017.11.005

    Article  CAS  Google Scholar 

  49. Corbo C, Orrù S, Salvatore F (2013) SRp20: An overview of its role in human diseases. Biochem Biophys Res Commun 436(1):1–5

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China (No. 81773044), Science and Technology Special Project of Clinical Medicine in Jiangsu Province (BL2014046), Social Development Project of Jiangsu Province (BE2019657), Qinglan Project of Jiangsu Province, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Author notes

  1. Chunxia Zhang, Yinshuang Chen and Fuchao Li contributed equally to this work.

Authors and Affiliations

  1. Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Building #1339, Wenjing Road, Suzhou Industrial Park, Suzhou, 215123, China

    Chunxia Zhang, Yinshuang Chen, Man Yang, Fanyi Meng, Yawen Zhang & Weipeng Wang

  2. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, 215006, China

    Chunxia Zhang, Weichang Chen & Weipeng Wang

  3. Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Chunxia Zhang, Weichang Chen & Weipeng Wang

  4. Department of Gerontology, The Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, China

    Fuchao Li

  5. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Shizhi Street 188, Suzhou, 215006, China

    Weichang Chen

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  1. Chunxia Zhang
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Contributions

WPW and CWC conceived the idea and directed the study. ZCX, CYS, LFC, CWC, and WPW designed the experiments and wrote the manuscript. ZCX, CYS, LFC, MY, FYM, and ZYW performed experiments. ZCX, CYS, and LFC analyzed the data. ZCX, CYS, LFC, CWC, and WPW generated figures. CWC and WPW critically revised the manuscript for important intellectual content.

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Correspondence to Weichang Chen or Weipeng Wang.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of Soochow University (No.IRB-29-20120512H) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Zhang, C., Chen, Y., Li, F. et al. B7-H3 is spliced by SRSF3 in colorectal cancer. Cancer Immunol Immunother 70, 311–321 (2021). https://doi.org/10.1007/s00262-020-02683-9

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