High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer

Chen,Yahua; Liu,Jun; Wang,Wei; Xiang,Li; Wang,Jide; Liu,Side; Zhou,Hongyan; Guo,Zheng

doi:10.3892/or.2018.6273

High expression of hnRNPA1 promotes cell invasion by inducing EMT in gastric cancer

Authors:
- Yahua Chen
- Jun Liu
- Wei Wang
- Li Xiang
- Jide Wang
- Side Liu
- Hongyan Zhou
- Zheng Guo
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Affiliations: Department of Gastroenterology, Longgang People's Hospital, Shenzhen, Guangdong 518172, P.R. China, Department of Pathology, The First People's Hospital of Xinxiang City, Xinxiang, Henan 453100, P.R. China, Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
Published online on: February 16, 2018 https://doi.org/10.3892/or.2018.6273
Pages: 1693-1701
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Advanced gastric cancer (GC) has a poor prognosis and its treatment strategies are not very efficient. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) has emerged as a plausible GC marker, however the role and molecular mechanism of hnRNPA1 in cell invasion and migration remains unknown. In the present study, the gene expression across normal and tumor tissue (GENT) database was used to evaluate the mRNA expression of hnRNPA1 in various types of cancer. Western blot analysis (WB) and immunohistochemistry (IHC) were performed to detect the protein expression of hnRNPA1 in GC tissues and adjacent non‑tumor tissues. The expression of multiple oncogenes was detected by western blot analysis and quantitative RT‑PCR in hnRNPA1 overexpressing GC cells. Soft agar colony formation, EdU incorporation, wound healing and invasion assays were applied to verify the role of hnRNPA1 in anchorage‑independent cell growth, migration and invasion in GC cells. Epithelial‑to‑mesenchymal transition (EMT) markers were detected by immunofluorescence, western blot analysis and IHC in vitro. A nude mice model of metastasis carcinoma was established to confirm the role of hnRNPA1 during EMT in vivo. Our results revealed that hnRNPA1 was significantly upregulated in GC tissue. HnRNPA1 overexpression significantly induced cell growth, migration and invasion ability in GC cells. In addition, hnRNPA1 promoted EMT of GC cells in vitro and in vivo. These findings indicated that hnRNPA1 is highly expressed in GC and promoted invasion by inducing EMT transition in GC cells. Thus, hnRNPA1 may be a potential therapeutic target for GC.

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1	Carcas LP: Gastric cancer review. J Carcinog. 13:142014. View Article : Google Scholar : PubMed/NCBI
2	Houghton J, Fox JG and Wang TC: Gastric cancer: Laboratory bench to clinic. J Gastroenterol Hepatol. 17:495–502. 2002. View Article : Google Scholar : PubMed/NCBI
3	Strickler JG, Zheng J, Shu Q, Burgart LJ, Alberts SR and Shibata D: p53 mutations and microsatellite instability in sporadic gastric cancer: When guardians fail. Cancer Res. 54:4750–4755. 1994.PubMed/NCBI
4	Zheng L, Wang L, Ajani J and Xie K: Molecular basis of gastric cancer development and progression. Gastric Cancer. 7:61–77. 2004. View Article : Google Scholar : PubMed/NCBI
5	Zeng H, Zheng R, Guo Y, Zhang S, Zou X, Wang N, Zhang L, Tang J, Chen J, Wei K, et al: Cancer survival in China, 2003–2005: A population-based study. Int J Cancer. 136:1921–1930. 2015. View Article : Google Scholar : PubMed/NCBI
6	Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, et al: D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. 359:453–462. 2008. View Article : Google Scholar : PubMed/NCBI
7	Chen HH, Chang JG, Lu RM, Peng TY and Tarn WY: The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Mol Cell Biol. 28:6929–6938. 2008. View Article : Google Scholar : PubMed/NCBI
8	Ostareck-Lederer A, Ostareck DH, Cans C, Neubauer G, Bomsztyk K, Superti-Furga G and Hentze MW: c-Src-mediated phosphorylation of hnRNP K drives translational activation of specifically silenced mRNAs. Mol Cell Biol. 22:4535–4543. 2002. View Article : Google Scholar : PubMed/NCBI
9	Zhou ZJ, Dai Z, Zhou SL, Fu XT, Zhao YM, Shi YH, Zhou J and Fan J: Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer. 132:1080–1089. 2013. View Article : Google Scholar : PubMed/NCBI
10	Sueoka E, Goto Y, Sueoka N, Kai Y, Kozu T and Fujiki H: Heterogeneous nuclear ribonucleoprotein B1 as a new marker of early detection for human lung cancers. Cancer Res. 59:1404–1407. 1999.PubMed/NCBI
11	Loh TJ, Moon H, Cho S, Jang H, Liu YC, Tai H, Jung DW, Williams DR, Kim HR, Shin MG, et al: CD44 alternative splicing and hnRNP A1 expression are associated with the metastasis of breast cancer. Oncol Rep. 34:1231–1238. 2015. View Article : Google Scholar : PubMed/NCBI
12	Yu C, Guo J, Liu Y, Jia J, Jia R and Fan M: Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation. J Cell Physiol. 230:2252–2261. 2015. View Article : Google Scholar : PubMed/NCBI
13	Torosyan Y, Dobi A, Glasman M, Mezhevaya K, Naga S, Huang W, Paweletz C, Leighton X, Pollard HB and Srivastava M: Role of multi-hnRNP nuclear complex in regulation of tumor suppressor ANXA7 in prostate cancer cells. Oncogene. 29:2457–2466. 2010. View Article : Google Scholar : PubMed/NCBI
14	Liu X, Zhou Y, Lou Y and Zhong H: Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell cycle arrest at G0/G1 phase. Gene. 576:791–797. 2016. View Article : Google Scholar : PubMed/NCBI
15	Qing S, Tulake W, Ru M, Li X, Yuemaier R, Lidifu D, Rouzibilali A, Hasimu A, Yang Y, Rouziahong R, et al: Proteomic identification of potential biomarkers for cervical squamous cell carcinoma and human papillomavirus infection. Tumour Biol. 39:10104283176975472017. View Article : Google Scholar : PubMed/NCBI
16	Hermann R, Hensel F, Müller EC, Keppler M, Souto-Carneiro M, Brändlein S, Müller-Hermelink HK and Vollmers HP: Deactivation of regulatory proteins hnRNP A1 and A2 during SC-1 induced apoptosis. Hum Antibodies. 10:83–90. 2001.PubMed/NCBI
17	Guo Z, Zhang W, Xia G, Niu L, Zhang Y, Wang X, Zhang Y, Jiang B and Wang J: Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation. Mol Carcinog. 49:826–836. 2010.PubMed/NCBI
18	Wu Y, Guo Z, Zhang D, Zhang W, Yan Q, Shi X, Zhang M, Zhao Y, Zhang Y, Jiang B, et al: A novel colon cancer gene therapy using rAAV-mediated expression of human shRNA-FHL2. Int J Oncol. 43:1618–1626. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhang W, Guo Z, Jiang B, Niu L, Xia G, Wang X, Cheng T, Zhang Y and Wang J: Identification of a functional p53 responsive element within the promoter of XAF1 gene in gastrointestinal cancer cells. Int J Oncol. 36:1031–1037. 2010.PubMed/NCBI
20	Guo Z, Zhou Y, Evers BM and Wang Q: Rictor regulates FBXW7-dependent c-Myc and cyclin E degradation in colorectal cancer cells. Biochem Biophys Res Commun. 418:426–432. 2012. View Article : Google Scholar : PubMed/NCBI
21	Zhang W, Jiang B, Guo Z, Sardet C, Zou B, Lam CS, Li J, He M, Lan HY, Pang R, et al: Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer. Carcinogenesis. 31:1220–1229. 2010. View Article : Google Scholar : PubMed/NCBI
22	Shin KH, Kang MK, Kim RH, Christensen R and Park NH: Heterogeneous nuclear ribonucleoprotein G shows tumor suppressive effect against oral squamous cell carcinoma cells. Clin Cancer Res. 12:3222–3228. 2006. View Article : Google Scholar : PubMed/NCBI
23	Gumireddy K, Li A, Gimotty PA, Klein-Szanto AJ, Showe LC, Katsaros D, Coukos G, Zhang L and Huang Q: KLF17 is a negative regulator of epithelial-mesenchymal transition and metastasis in breast cancer. Nat Cell Biol. 11:1297–1304. 2009. View Article : Google Scholar : PubMed/NCBI
24	Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC and Wu KJ: Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 10:295–305. 2008. View Article : Google Scholar : PubMed/NCBI
25	Park WC, Kim HR, Kang DB, Ryu JS, Choi KH, Lee GO, Yun KJ, Kim KY, Park R, Yoon KH, et al: Comparative expression patterns and diagnostic efficacies of SR splicing factors and HNRNPA1 in gastric and colorectal cancer. BMC Cancer. 16:3582016. View Article : Google Scholar : PubMed/NCBI
26	Zhou B, Wang Y, Jiang J, Jiang H, Song J, Han T, Shi J and Qiao H: The long noncoding RNA colon cancer-associated transcript-1/miR-490 axis regulates gastric cancer cell migration by targeting hnRNPA1. IUBMB Life. 68:201–210. 2016. View Article : Google Scholar : PubMed/NCBI
27	Bonomi S, di Matteo A, Buratti E, Cabianca DS, Baralle FE, Ghigna C and Biamonti G: HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition. Nucleic Acids Res. 41:8665–8679. 2013. View Article : Google Scholar : PubMed/NCBI
28	Tauler J, Zudaire E, Liu H, Shih J and Mulshine JL: hnRNP A2/B1 modulates epithelial-mesenchymal transition in lung cancer cell lines. Cancer Res. 70:7137–7147. 2010. View Article : Google Scholar : PubMed/NCBI
29	Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL and Howe PH: TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nature Cell Biol. 12:286–293. 2010.PubMed/NCBI
30	Zhou ZJ, Dai Z, Zhou SL, Hu ZQ, Chen Q, Zhao YM, Shi YH, Gao Q, Wu WZ, Qiu SJ, et al: HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL. Cancer Res. 74:2750–2762. 2014. View Article : Google Scholar : PubMed/NCBI
31	Ratz L, Laible M, Kacprzyk LA, Wittig-Blaich SM, Tolstov Y, Duensing S, Altevogt P, Klauck SM and Sültmann H: TMPRSS2:ERG gene fusion variants induce TGF-β signaling and epithelial to mesenchymal transition in human prostate cancer cells. Oncotarget. 8:25115–25130. 2017. View Article : Google Scholar : PubMed/NCBI
32	Chandra Mangalhara K, Manvati S, Saini SK, Ponnusamy K, Agarwal G, Abraham SK and Bamezai RNK: ERK2-ZEB1-miR-101-1 axis contributes to epithelial-mesenchymal transition and cell migration in cancer. Cancer Lett. 391:59–73. 2017. View Article : Google Scholar : PubMed/NCBI
33	Bucay N, Bhagirath D, Sekhon K, Yang T, Fukuhara S, Majid S, Shahryari V, Tabatabai Z, Greene KL, Hashimoto Y, et al: A novel microRNA regulator of prostate cancer epithelial-mesenchymal transition. Cell Death Differ. 24:1263–1274. 2017. View Article : Google Scholar : PubMed/NCBI
34	Zhao J, Ou B, Han D, Wang P, Zong Y, Zhu C, Liu D, Zheng M, Sun J, Feng H, et al: Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer. 16:702017. View Article : Google Scholar : PubMed/NCBI