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http://dx.doi.org/10.5483/BMBRep.2022.55.7.034

Alternative splicing variant of NRP/B promotes tumorigenesis of gastric cancer  

Kim, Aram (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University)
Mok, Bo Ram (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University)
Hahn, Soojung (Department of Microbiology, Institution of Basic Medical Science, School of Medicine, CHA University)
Yoo, Jongman (Department of Microbiology, Institution of Basic Medical Science, School of Medicine, CHA University)
Kim, Dong Hyun (Department of Dermatology, Bundang CHA Medical Center, School of Medicine, CHA University)
Kim, Tae-Aug (Department of Biochemistry, Institution of Basic Medical Science, School of Medicine, CHA University)
Publication Information
BMB Reports / v.55, no.7, 2022 , pp. 348-353 More about this Journal
Abstract
Gastrointestinal cancer is associated with a high mortality rate. Here, we report that the splice variant of NRP/B contributes to tumorigenic activity in highly malignant gastric cancer through dissociation from the tumor repressor, HDAC5. NRP/B mRNA expression is significantly higher in the human gastric cancer tissues than in the normal tissues. Further, high levels of both the NRP/B splice variant and Lgr5, but not the full-length protein, are found in highly tumorigenic gastric tumor cells, but not in non-tumorigenic cells. The loss of NRP/B markedly inhibits cell migration and invasion, which reduces tumor formation in vivo. Importantly, the inhibition of alternative splicing increases the levels of NRP/B-1 mRNA and protein in AGS cells. The ectopic expression of full-length NRP/B exhibits tumor-suppressive activity, whereas NRP/B-2 induces the noninvasive human gastric cancer cells tumorigenesis. The splice variant NRP/B-2 which loses the capacity to interact with tumor repressors promoted oncogenic activity, suggesting that the BTB/POZ domain in the N-terminus has a crucial role in the suppression of gastric cancer. Therefore, the regulation of alternative splicing of the NRP/B gene is a potential novel target for the treatment of gastrointestinal cancer.
Keywords
Alternative splicing; Gastric cancer; HDAC5; Lgr5; NRP/B;
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1 Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674   DOI
2 Polyak K, Xia Y, Zweier JL et al (1997) A model for p53-induced apoptosis. Nature 389, 300-305   DOI
3 Ye M, Fang Z, Gu H et al (2017) Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition. Tumour Biol 39, 1010428317705034
4 Jang BG, Kim HS, Chang WY et al (2018) Expression profile of LGR5 and its prognostic significance in colorectal cancer progression. Am J Pathol 188, 2236-2250   DOI
5 Brown RL, Reinke LM, Damerow MS et al (2011) CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 121, 1064-1074   DOI
6 Lapointe J, Li C, Higgins JP et al (2004) Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A 101, 811-816   DOI
7 Skotheim RI and Nees M (2007) Alternative splicing in cancer: noise, functional, or systematic. Int J Biochem Cell Biol 39, 1432-1449   DOI
8 Choi J, Yang ES, Cha K et al (2014) The nuclear matrix protein, NRP/B, acts as a transcriptional repressor of E2Fmediated transcriptional activity. J cancer Prev 19, 187-198   DOI
9 Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72, 291-336   DOI
10 Liu S and Cheng C (2013) Alternative RNA splicing and cancer. Wiley Interdiscip Rev RNA 4, 547-566
11 Fackenthal JD and Godley LA (2008) Aberrant RNA splicing and its functional consequences in cancer cells. Dis Model Mech 1, 37-42   DOI
12 Sveen A, Kilpinen S, Ruusulehto A et al (2016) RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene 35, 2413-2427   DOI
13 Choi HY, Seok J, Kang GH, Lim KM, Cho SG (2021) The role of NUMB/NUMB isoforms in cancer stem cells. BMB Rep 54, 335-343   DOI
14 Mustelin T, Rahmouni S, Bottini N et al (2003) Role of protein tyrosine phosphatases in T cell activation. Immunol Rev 191, 139-147   DOI
15 Cascino I, Fiucci G, Papoff G et al (1995) Three functional soluble forms of the human apoptosis-inducing Fas molecule are produced by alternative splicing. J Immunol 154, 2706-2713   DOI
16 Orian-Rousseau V, Chen L, Sleeman JP et al (2002) CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16, 3074-3086   DOI
17 Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353-364   DOI
18 Wong MS, Chen L, Foster C et al (2013) Regulation of telomerase alternative splicing: a target for chemotherapy. Cell Rep 3, 1028-1035   DOI
19 Jurica MS, Mesecar A, Heath P et al (1998) The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 6, 195-210   DOI
20 Murray-Zmijewski F, Lane DP, Bourdon J-C (2006) p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 13, 962-972   DOI
21 Chen C, Zhao S, Karnad A et al (2018) The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol 11, 64   DOI
22 Kim TA, Lim J, Ota S et al (1998) NRP/B, a novel nuclear matrix protein, associates with p110(RB) and is involved in neuronal differentiation. J Cell Biol 141, 553-566   DOI
23 Lee KH, Choi EY, Kim MK et al (2010) Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer. Mol Cell Biochem 343, 163-171   DOI
24 Fujita M, Furukawa Y, Tsunoda et al (2001) Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the beta-catenin/T-cell factor complex, in colorectal carcinomas. Cancer Res 61, 7722-7726
25 Godt D, Couderc JL, Cramton SE et al (1993) Pattern formation in the limbs of Drosophila: bric a brac is expressed in both a gradient and a wave-like pattern and is required for specification and proper segmentation of the tarsus. Development 119, 799-812   DOI
26 Worton LE, Shi YC, Smith EJ et al (2017) Ar ticle Ectodermal-neural cortex 1 isoforms have contrasting effects on MC3T3-E1 osteoblast mineralization and gene expression. J Cell Biochem 118, 2141-2150   DOI
27 Singh S, Narayanan SP, Biswas K et al (2017) Intragenic DNA methylation and BORIS-mediated cancer-specific splicing contribute to the Warburg effect. Proc Natl Acad Sci U S A 114,11440-11445   DOI
28 Qi Z, Li Y, Zhao B et al (2017) BMP restricts stemness of intestinal Lgr5+ stem cells by directly suppressing their signature genes. Nat Commun 8, 13824   DOI
29 Li XB, Yang G, Zhu L et al (2016) Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice. Cell Res 26, 838-849   DOI
30 Yin X, Farin HF, Es JH et al (2014) Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat Methods 11, 106-112   DOI
31 Xu P, Dang Y, Wang L et al (2016) Lgr4 is crucial for skin carcinogenesis by regulating MEK/ERK and Wnt/β-catenin signaling pathways. Cancer Lett 383, 161-170   DOI
32 Yokota N, Mainprize TG, Taylor MD et al (2004) Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization. Oncogene 23, 3444-3453   DOI
33 Kim TA, Ota S, Jiang S et al (2000) Genomic organization, chromosomal localization and regulation of expression of the neuronal nuclear matrix protein NRP/B in human brain tumors. Gene 255, 105-116   DOI