FABP5 regulates the proliferation of clear cell renal cell carcinoma cells via the PI3K/AKT signaling pathway

Lv,Qi; Wang,Gangmin; Zhang,Yinan; Han,Xiao; Li,Haoming; Le,Wei; Zhang,Minguang; Ma,Chunhui; Wang,Peijun; Ding,Qiang

doi:10.3892/ijo.2019.4721

FABP5 regulates the proliferation of clear cell renal cell carcinoma cells via the PI3K/AKT signaling pathway

Authors:
- Qi Lv
- Gangmin Wang
- Yinan Zhang
- Xiao Han
- Haoming Li
- Wei Le
- Minguang Zhang
- Chunhui Ma
- Peijun Wang
- Qiang Ding
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Affiliations: Imaging Department of Tongji Hospital, Medical School of Tongji University, Shanghai 200065, P.R. China, Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Urology, Shandong Province affiliated Hospital, Shandong University, Jinan, Shandong 250021, P.R. China, Department of Human Anatomy, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Orthopedic Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, P.R. China
Published online on: February 22, 2019 https://doi.org/10.3892/ijo.2019.4721
Pages: 1221-1232
Copyright: © Lv et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Clear cell renal cell carcinoma (ccRCC) has been associated with one of the highest mortality rates among all cancers. Fatty acid binding proteins (FABPs) are 14‑15 kDa proteins that are highly abundant in the cytosol of most tissues. FABP5, a member of the FABP family, has been observed to promote tumor cell growth in numerous cancer types. In order to investigate the function of FABP5 in ccRCC cells in the present study, RNA sequencing data from The Cancer Genome Atlas were analyzed to determine the expression levels of FABP5 in ccRCC patient samples. Survival and Cox regression analyses were performed to measure the association between FABP5 expression and clinicopathological features of patients with ccRCC. Subsequent in vitro experiments downregulated or overexpressed FABP5 in Caki‑1 and 786O ccRCC cells using lentiviral vectors to evaluate cell proliferation ability, and a xenograft transplantation model was established to examine the effect of FABP5 on tumorigenesis in vivo. The results demonstrated that FABP5 expression was significantly upregulated in samples from patients with ccRCC when compared with normal tissue samples. High FABP5 expression was also significantly correlated with tumor and metastasis classifications and predicted poor survival in patients with ccRCC. In ccRCC cells, silencing of FABP5 significantly inhibited cell proliferation, while overexpression of FABP5 promoted cell proliferation when compared to the respective controls. In addition, treatment with the phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K)/AKT inhibitor, LY294002, attenuated the pro‑proliferative effects of exogenous FABP5 expression in Caki‑1 and 786O cells. This indicated that the PI3K/AKT signaling pathway may be partially involved in the FABP5‑mediated increase in ccRCC cell proliferation. Furthermore, FABP5 was observed to regulate tumor growth in nude mice in vivo. In conclusion, the results of the present study suggest that FABP5 may exert a pro‑proliferative role in ccRCC and may be associated with malignant progression and tumorigenesis.

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1	Volpe A and Patard JJ: Prognostic factors in renal cell carcinoma. World J Urol. 28:319–327. 2010. View Article : Google Scholar : PubMed/NCBI
2	Wood LS: Renal cell carcinoma: Screening, diagnosis, and prognosis. Clin J Oncol Nurs. 13:3–7. 2009. View Article : Google Scholar : PubMed/NCBI
3	Cheville JC, Lohse CM, Zincke H, Weaver AL and Blute ML: Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 27:612–624. 2003. View Article : Google Scholar : PubMed/NCBI
4	Levy DA, Slaton JW, Swanson DA and Dinney CP: Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol. 159:1163–1167. 1998. View Article : Google Scholar : PubMed/NCBI
5	Figlin RA: Renal cell carcinoma: Management of advanced disease. J Urol. 161:381–386; discussion 386–387 1999. PubMed/NCBI
6	Zhong C, Chen Y, Tao B, Peng L, Peng T, Yang X, Xia X and Chen L: LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway. BMC Cancer. 18:7222018. View Article : Google Scholar : PubMed/NCBI
7	Shen GY, Ren H, Huang JJ, Zhang ZD, Zhao WH, Yu X, Shang Q, Qiu T, Zhang YZ, Tang JJ, et al: Plastrum Testudinis Extracts Promote BMSC Proliferation and Osteogenic Differentiation by Regulating Let-7f–5p and the TNFR2/PI3K/AKT Signaling Pathway. Cell Physiol Biochem. 47:2307–2318. 2018. View Article : Google Scholar
8	Hou T, Zhou L, Wang L, Kazobinka G, Chen Y, Zhang X and Chen Z: Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway. Cell Physiol Biochem. 47:2250–2260. 2018. View Article : Google Scholar : PubMed/NCBI
9	Wang Y, Wang W, Li D, Li M, Wang P, Wen J, Liang M, Su B and Yin Y: IGF-1 alleviates NMDA-induced excitotoxicity in cultured hippocampal neurons against autophagy via the NR2B/PI3K-AKT-mTOR pathway. J Cell Physiol. 229:1618–1629. 2014. View Article : Google Scholar : PubMed/NCBI
10	Xu W, Yang Z and Lu N: A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adhes Migr. 9:317–324. 2015. View Article : Google Scholar
11	Sun P, Wang L, Lu Y, Liu Y, Li L, Yin L, Zhang C, Zhao W, Shen B and Xu W: MicroRNA-195 targets VEGFR2 and has a tumor suppressive role in ACHN cells via PI3K/Akt and Raf/MEK/ERK signaling pathways. Int J Oncol. 49:1155–1163. 2016. View Article : Google Scholar : PubMed/NCBI
12	Zhou J, Zhu G, Huang J, Li L, Du Y, Gao Y, Wu D, Wang X, Hsieh JT, He D, et al: Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: A novel potential therapeutic target. Cancer Lett. 370:313–323. 2016. View Article : Google Scholar
13	Gajda AM and Storch J: Enterocyte fatty acid-binding proteins (FABPs): Different functions of liver and intestinal FABPs in the intestine. Prostaglandins Leukot Essent Fatty Acids. 93:9–16. 2015. View Article : Google Scholar
14	Storch J and Corsico B: The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 28:73–95. 2008. View Article : Google Scholar : PubMed/NCBI
15	Richieri GV, Ogata RT, Zimmerman AW, Veerkamp JH and Kleinfeld AM: Fatty acid binding proteins from different tissues show distinct patterns of fatty acid interactions. Biochemistry. 39:7197–7204. 2000. View Article : Google Scholar : PubMed/NCBI
16	Maximin E, Langelier B, Aïoun J, Al-Gubory KH, Bordat C, Lavialle M and Heberden C: Fatty acid binding protein 7 and n-3 p oly unsaturated fatty acid supply in early rat brain development. Dev Neurobiol. 76:287–297. 2016. View Article : Google Scholar
17	Lin H, Patel S, Affleck VS, Wilson I, Turnbull DM, Joshi AR, Maxwell R and Stoll EA: Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells. Neuro-oncol. 19:43–54. 2017. View Article : Google Scholar :
18	Wang W, Chu HJ, Liang YC, Huang JM, Shang CL, Tan H, Liu D, Zhao YH, Liu TY and Yao SZ: FABP5 correlates with poor prognosis and promotes tumor cell growth and metastasis in cervical cancer. Tumour Biol. 37:14873–14883. 2016. View Article : Google Scholar : PubMed/NCBI
19	Wang W, Jia HL, Huang JM, Liang YC, Tan H, Geng HZ, Guo LY and Yao SZ: Identification of biomarkers for lymph node metastasis in early-stage cervical cancer by tissue-based proteomics. Br J Cancer. 110:1748–1758. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhao G, Wu M, Wang X, Du Z and Zhang G: Effect of FABP5 gene silencing on the proliferation, apoptosis and invasion of human gastric SGC-7901 cancer cells. Oncol Lett. 14:4772–4778. 2017. View Article : Google Scholar : PubMed/NCBI
21	Ohata T, Yokoo H, Kamiyama T, Fukai M, Aiyama T, Hatanaka Y, Hatanaka K, Wakayama K, Orimo T, Kakisaka T, et al: Fatty acid-binding protein 5 function in hepatocellular carcinoma through induction of epithelial-mesenchymal transition. Cancer Med. 6:1049–1061. 2017. View Article : Google Scholar : PubMed/NCBI
22	Wang W, Zhang M, Peng Y and He J: Ubiquitin Associated Protein 2-Like (UBAP2L) Overexpression in Patients with Hepatocellular Carcinoma and its Clinical Significance. Med Sci Monit. 23:4779–4788. 2017. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) μethod. Methods. 25:402–408. 2001. View Article : Google Scholar
24	Han X, Li H, Zhang Y, Qin J, Yang Q, Wang L, Yuan M and Xia C: Brain lipid-binding protein promotes proliferation and modulates cell cycle in C6 rat glioma cells. Int J Oncol. 51:1439–1448. 2017. View Article : Google Scholar : PubMed/NCBI
25	Jiang N, Meng C, Han X, Guo J, Li H and Yu Z: Low-dose cisplatin causes growth inhibition and loss of autophagy of rat astrocytes in vitro. Neurosci Lett. 682:112–117. 2018. View Article : Google Scholar : PubMed/NCBI
26	Shi H, Xu J, Zhao R, Wu H, Gu L and Chen Y: FGF2 regulates proliferation, migration, and invasion of ECA109 cells through PI3K/Akt signalling pathway in vitro. Cell Biol Int. 40:524–533. 2016. View Article : Google Scholar : PubMed/NCBI
27	Leary S, Underwood W, Anthony R, Cartner S, Corey D, Grandin T, Greenacre CB, Gwaltney-Bran S, McCrackin MA and Meyer R: AVMA Guidelines for the Euthanasia of Animals. 2013 Edition. University of Alaska Anchorage; Schaumburg: 2013
28	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
29	Zhang W, Chen R, Yang T, Xu N, Chen J, Gao Y and Stetler RA: Fatty acid transporting proteins: Roles in brain development, aging, and stroke. Prostaglandins Leukot Essent Fatty Acids. 136:35–45. 2018. View Article : Google Scholar
30	Berk PD, Wada H, Horio Y, Potter BJ, Sorrentino D, Zhou SL, Isola LM, Stump D, Kiang CL and Thung S: Plasma membrane fatty acid-binding protein and mitochondrial glutamic-oxalo-acetic transaminase of rat liver are related. Proc Natl Acad Sci USA. 87:3484–3488. 1990. View Article : Google Scholar
31	Stremmel W, Kochwa S and Berk PD: Studies of oleate binding to rat liver plasma membranes. Biochem Biophys Res Commun. 112:88–95. 1983. View Article : Google Scholar : PubMed/NCBI
32	Storch J and Thumser AE: The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta. 1486:28–44. 2000. View Article : Google Scholar : PubMed/NCBI
33	Matsumata M, Sakayori N, Maekawa M, Owada Y, Yoshikawa T and Osumi N: The effects of Fabp7 and Fabp5 on postnatal hippocampal neurogenesis in the mouse. Stem Cells. 30:1532–1543. 2012. View Article : Google Scholar : PubMed/NCBI
34	Amiri M, Yousefnia S, Seyed Forootan F, Peymani M, Ghaedi K and Nasr Esfahani MH: Diverse roles of fatty acid binding proteins (FABPs) in development and pathogenesis of cancers. Gene. 676:171–183. 2018. View Article : Google Scholar : PubMed/NCBI
35	Boiteux G, Lascombe I, Roche E, Plissonnier ML, Clairotte A, Bittard H and Fauconnet S: A-FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cells. Int J Cancer. 124:1820–1828. 2009. View Article : Google Scholar
36	Schug TT, Berry DC, Toshkov IA, Cheng L, Nikitin AY and Noy N: Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARbeta/delta to RAR. Proc Natl Acad Sci USA. 105:7546–7551. 2008. View Article : Google Scholar : PubMed/NCBI
37	Morgan E, Kannan-Thulasiraman P and Noy N: Involvement of Fatty Acid Binding Protein 5 and PPARβ/δ in Prostate Cancer Cell Growth. PPAR Res. 2010.pii: 234629. 2010. View Article : Google Scholar
38	De Rosa A, Pellegatta S, Rossi M, Tunici P, Magnoni L, Speranza MC, Malusa F, Miragliotta V, Mori E, Finocchiaro G, et al: A radial glia gene marker, fatty acid binding protein 7 (FABP7), is involved in proliferation and invasion of glioblastoma cells. PLoS One. 7:e521132012. View Article : Google Scholar
39	Lee D, Wada K, Taniguchi Y, Al-Shareef H, Masuda T, Usami Y, Aikawa T, Okura M, Kamisaki Y and Kogo M: Expression of fatty acid binding protein 4 is involved in the cell growth of oral squamous cell carcinoma. Oncol Rep. 31:1116–1120. 2014. View Article : Google Scholar : PubMed/NCBI
40	Ku CY, Liu YH, Lin HY, Lu SC and Lin JY: Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma. Oncotarget. 7:18229–18246. 2016. View Article : Google Scholar : PubMed/NCBI
41	Song GX, Shen YH, Liu YQ, Sun W, Miao LP, Zhou LJ, Liu HL, Yang R, Kong XQ, Cao KJ, et al: Overexpression of FABP3 promotes apoptosis through inducing mitochondrial impairment in embryonic cancer cells. J Cell Biochem. 113:3701–3708. 2012. View Article : Google Scholar : PubMed/NCBI
42	Liang Y, Bollen AW, Aldape KD and Gupta N: Nuclear FABP7 immunoreactivity is preferentially expressed in infiltrative glioma and is associated with poor prognosis in EGFR-overexpressing glioblastoma. BMC Cancer. 6:972006. View Article : Google Scholar : PubMed/NCBI
43	Kawaguchi K, Kinameri A, Suzuki S, Senga S, Ke Y and Fujii H: The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis. Biochem J. 473:449–461. 2016. View Article : Google Scholar
44	Forootan FS, Forootan SS, Gou X, Yang J, Liu B, Chen D, Al Fayi MS, Al-Jameel W, Rudland PS, Hussain SA, et al: Fatty acid activated PPARγ promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter. Oncotarget. 7:9322–9339. 2016. View Article : Google Scholar : PubMed/NCBI
45	Levi L, Lobo G, Doud MK, von Lintig J, Seachrist D, Tochtrop GP and Noy N: Genetic ablation of the fatty acid-binding protein FABP5 suppresses HER2-induced mammary tumorigenesis. Cancer Res. 73:4770–4780. 2013. View Article : Google Scholar : PubMed/NCBI
46	Powell CA, Nasser MW, Zhao H, Wochna JC, Zhang X, Shapiro C, Shilo K and Ganju RK: Fatty acid binding protein 5 promotes metastatic potential of triple negative breast cancer cells through enhancing epidermal growth factor receptor stability. Oncotarget. 6:6373–6385. 2015. View Article : Google Scholar : PubMed/NCBI
47	Kawaguchi K, Senga S, Kubota C, Kawamura Y, Ke Y and Fujii H: High expression of Fatty Acid-Binding Protein 5 promotes cell growth and metastatic potential of colorectal cancer cells. FEBS Open Bio. 6:190–199. 2016. View Article : Google Scholar : PubMed/NCBI
48	Ciruelos Gil EM: Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev. 40:862–871. 2014. View Article : Google Scholar : PubMed/NCBI
49	Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, Dharmarajan AM, Sethi G and Kumar AP: Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine? World J Gastroenterol. 21:12261–12273. 2015. View Article : Google Scholar : PubMed/NCBI
50	Polivka J Jr and Janku F: Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 142:164–175. 2014. View Article : Google Scholar
51	Fumarola C, Bonelli MA, Petronini PG and Alfieri RR: Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 90:197–207. 2014. View Article : Google Scholar : PubMed/NCBI
52	Guo H, German P, Bai S, Barnes S, Guo W, Qi X, Lou H, Liang J, Jonasch E, Mills GB, et al: The PI3K/AKT Pathway and Renal Cell Carcinoma. J Genet Genomics. 42:343–353. 2015. View Article : Google Scholar : PubMed/NCBI
53	Apanovich NV, Peters MV, Apanovich PV, Kamolov BS, Matveev VB, Ginter EK and Karpukhin AV: Expression Profiles of Genes-Potential Therapy Targets-and Their Relationship to Survival in Renal Cell Carcinoma. Dokl Biochem Biophys. 478:14–17. 2018. View Article : Google Scholar : PubMed/NCBI
54	Xu L, Zhu Y, Xu J, Wu K, Li J, Xu W, Liu H, Wang S, Yin H, Chen L, et al: Notch1 activation promotes renal cell carcinoma growth via PI3K/Akt signaling. Cancer Sci. 103:1253–1258. 2012. View Article : Google Scholar : PubMed/NCBI
55	Liu S, Ma X, Ai Q, Huang Q, Shi T, Zhu M, Wang B and Zhang X: NOTCH1 functions as an oncogene by regulating the PTEN/PI3K/AKT pathway in clear cell renal cell carcinoma. Urol Oncol. 31:938–948. 2013. View Article : Google Scholar
56	Nogueira I, Dias F, Teixeira AL and Medeiros R: miRNAs as potential regulators of mTOR pathway in renal cell carcinoma. Pharmacogenomics. 19:249–261. 2018. View Article : Google Scholar : PubMed/NCBI
57	Xu Y, Tong Y, Zhu J, Lei Z, Wan L, Zhu X, Ye F and Xie L: An increase in long non-coding RNA PANDAR is associated with poor prognosis in clear cell renal cell carcinoma. BMC Cancer. 17:3732017. View Article : Google Scholar : PubMed/NCBI