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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Gastric Cancer | Primary research

hnRNPK promotes gastric tumorigenesis through regulating CD44E alternative splicing

Authors: Wei-zhao Peng, Ji-xi Liu, Chao-feng Li, Ren Ma, Jian-zheng Jie

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

The high prevalence of alternative splicing among genes implies the importance of genomic complexity in regulating normal physiological processes and diseases such as gastric cancer (GC). The standard form of stem cell marker CD44 (CD44S) and its alternatives with additional exons are reported to play important roles in multiple types of tumors, but the regulation mechanism of CD44 alternative splicing is not fully understood.

Methods

Here the expression of hnRNPK was analyzed among the Cancer Genome Atlas (TCGA) cohort of GC. The function of hnRNPK in GC cells was analyzed and its downstream targeted gene was identified by chromatin immunoprecipitation and dual luciferase report assay. Finally, effect of hnRNPK and its downstream splicing regulator on CD44 alternative splicing was investigated.

Results

The expression of hnRNPK was significantly increased in GC and its upregulation was associated with tumor stage and metastasis. Loss-of-function studies found that hnRNPK could promote GC cell proliferation, migration, and invasion. The upregulation of hnRNPK activates the expression of the splicing regulator SRSF1 by binding to the first motif upstream the start codon (− 65 to − 77 site), thereby increasing splicing activity and expression of an oncogenic CD44 isoform, CD44E (has additional variant exons 8 to 10, CD44v8-v10).

Conclusion

These findings revealed the importance of the hnRNPK-SRSF1-CD44E axis in promoting gastric tumorigenesis.
Appendix
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Literature
1.
2.
3.
Rawla P, et al. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol. 2019;14(1):26–38.PubMed
4.
Tozzi A, et al. Neoadjuvant chemoradiotherapy with volumetric-modulated arc therapy for medium-distal oesophageal and gastro-oesophageal junction carcinoma. Anticancer Res. 2015;35:4109–16.PubMed
5.
Lowenfeld L, et al. Multimodality treatment of T4 gastric cancer in the United States: utilization trends and impact on survival. Ann Surg Oncol. 2015;22(Suppl 3):S863–72.PubMedCrossRef
6.
7.
Hatakeyama K, et al. Identification of a novel protein isoform derived from cancer-related splicing variants using combined analysis of transcriptome and proteome. Proteomics. 2011;11(11):2275–82.PubMedCrossRef
8.
Miura K, et al. Alternative pre-mRNA splicing in digestive tract malignancy. Cancer Sci. 2011;102(2):309–16.PubMedCrossRef
9.
Luo C, et al. SRSF2 regulates alternative splicing to drive hepatocellular carcinoma development. Cancer Res. 2017;77(5):1168–78.PubMedCrossRef
10.
11.
Chen K, et al. Alternative splicing of EZH2 pre-mRNA by SF3B3 contributes to the tumorigenic potential of renal cancer. Clin Cancer Res. 2017;23(13):3428–41.PubMedCrossRef
12.
Matos P, et al. B-Raf(V600E) cooperates with alternativespliced Rac1b to sustain colorectal cancer cell survival. Gastroenterology. 2008;135:899–906.PubMedCrossRef
13.
da Cunha CB, et al. CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness. Biomaterials. 2016;98:152–62.CrossRef
14.
Patel S, et al. Insights into the structural perturbations of spliced variants of CD44: a modeling and simulation approach. J Biomol Struct Dyn. 2017;35(2):354–67.PubMedCrossRef
15.
Zhu S, et al. Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastrictumorigenesis. Oncogene. 2016;35(14):1847–56.PubMedCrossRef
16.
Zhang P, et al. CD82 suppresses CD44 alternative splicing-dependent melanoma metastasis by mediating U2AF2 ubiquitination and degradation. Oncogene. 2016;35(38):5056–69.PubMedPubMedCentralCrossRef
17.
Prochazka L, et al. Regulation of alternative splicing of CD44 in cancer. Cell Signal. 2014;26(10):2234–9.PubMedCrossRef
18.
Dong C, et al. Overexpression of c-fos promotes cell invasion and migration via CD44 pathway in oral squamous cell carcinoma. J Oral Pathol Med. 2015;44(5):353–60.PubMedCrossRef
19.
20.
Fan X, Xiong H, Wei J, Gao X, Feng Y, Liu X, et al. Cytoplasmic HNRNPK interacts with GSK3β and is essential for the osteoclast differentiation. Sci Rep. 2015;5:17732.PubMedPubMedCentralCrossRef
21.
Gao X, Feng J, He Y, Xu F, Fan X, Huang W, et al. HNRNPK inhibits GSK3β Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes toTRAIL resistance in H1299 lung adenocarcinoma cells. Sci Rep. 2016;6:22999.PubMedPubMedCentralCrossRef
22.
Gallardo M, et al. hnRNP K is a haploinsufficient tumor suppressor that regulates proliferation and differentiation programs in hematologic malignancies. Cancer Cell. 2015;28(4):486–99.PubMedPubMedCentralCrossRef
23.
Yang JH, et al. Arginine methylation of HNRNPK negatively modulates apoptosis upon DNA damage through local regulation of phosphorylation. Nucleic Acids Res. 2014;42(15):9908–24.PubMedPubMedCentralCrossRef
24.
Nika E, et al. hnRNP K in PU. 1-containing complexes recruited at the CD11b promoter: a distinct role in modulating granulocytic and monocytic differentiation of AML-derived cells. Biochem J. 2014;463(1):115–22.PubMedCrossRef
25.
Kim HR, et al. SRSF5: a novel marker for small-cell lung cancer and pleural metastatic cancer. Lung Cancer. 2016;99:57–65.PubMedCrossRef
26.
Park WC, Kim HR, Kang DB, Ryu JS, Choi KH, Lee GO, et al. Comparative expression patterns and diagnostic efficacies of SR splicing factors and HNRNPA1 in gastric and colorectal cancer. BMC Cancer. 2016;16:358.PubMedPubMedCentralCrossRef
27.
Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, et al. Genomic landscape survey identifies SRSF1 as a key oncodriver in small cell lung cancer. PLoS Genet. 2016;12(4):e1005895.PubMedPubMedCentralCrossRef
28.
Muramaki M, et al. Over expression of CD44V8-10 in human bladder cancer cells decreases their interactionwith hyaluronic acid and potentiates their malignant progression. J Urol. 2004;171(1):426–30.PubMedCrossRef
29.
30.
Eder S, et al. Baseline MAPK signaling activity confers intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K). Cancer Lett. 2017;385:160–7.PubMedCrossRef
31.
Chen X, et al. Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer. J Cell Mol Med. 2017;21(7):1266–79.PubMedCrossRef
32.
33.
Almeida LO, et al. Accumulated SET protein up-regulates and interacts with HNRNPK, increasing its binding to nucleic acids, the Bcl-xS repression, and cellular proliferation. Biochem Biophys Res Commun. 2014;445(1):196–202.PubMedCrossRef
34.
Karousou E, et al. Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer. Matrix Biol. 2017;59:3–22.PubMedCrossRef
35.
36.
37.
Omara-Opyene AL, et al. Prostate cancer invasion is influenced more by expression of a CD44 isoform including variant 9 than by Muc18. Lab Invest. 2004;84(7):894–907.PubMedCrossRef
38.
Seishima R, et al. Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9(+) cancer stem cells in ulcerative colitis-related cancer. Clin Res Hepatol Gastroenterol. 2016;40(4):487–93.PubMedCrossRef
39.
Go SI, et al. CD44 variant 9 serves as a poor prognostic marker in early gastric cancer, but not in advanced gastric cancer. Cancer Res Treat. 2016;48(1):142–52.PubMedCrossRef
40.
da Cunha CB, et al. De novo expression of CD44 variants in sporadic and hereditary gastric cancer. Lab Invest. 2010;90(11):1604–14.PubMedCrossRef
41.
Yamaguchi A, et al. Expression of variant CD44 containing variant exon v8–10 in gallbladder cancer. Oncol Rep. 2000;7(3):541–4.PubMed
Metadata
Title
hnRNPK promotes gastric tumorigenesis through regulating CD44E alternative splicing
Authors
Wei-zhao Peng
Ji-xi Liu
Chao-feng Li
Ren Ma
Jian-zheng Jie
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-1020-x

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