HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-β/Smad2 signaling pathway

Kou,Bo; Liu,Wei; Tang,Xiaoshuang; Kou,Qingshan

doi:10.3892/or.2017.6091

HMGA2 facilitates epithelial-mesenchymal transition in renal cell carcinoma by regulating the TGF-β/Smad2 signaling pathway

Authors:
- Bo Kou
- Wei Liu
- Xiaoshuang Tang
- Qingshan Kou
View Affiliations

Affiliations: Department of Cardiovascular Surgery, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Urology, Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Medical Center, First People's Hospital of Xianyang, Xianyang, Shaanxi 712000, P.R. China
Published online on: November 10, 2017 https://doi.org/10.3892/or.2017.6091
Pages: 101-108
Copyright: © Kou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E‑cadherin level was upregulated, while N‑cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786‑O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-β and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-β overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-β deficiency impeded the pro‑metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-β-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.

View Figures

View References

1	Fayaz MS, Al-Qaderi AE and El-Sherify MS: Metastatic renal cell carcinoma with undetectable renal mass presenting as lymphadenopathy. CEN Case Rep. 6:36–38. 2017. View Article : Google Scholar : PubMed/NCBI
2	Liu Y, Zeng S, Jiang X, Lai D and Su Z: SOX4 induces tumor invasion by targeting EMT-related pathway in prostate cancer. Tumour Biol. 39:10104283176945392017. View Article : Google Scholar : PubMed/NCBI
3	Chang JW, Gwak SY, Shim GA, Liu L, Lim YC, Kim JM, Jung MG and Koo BS: EZH2 is associated with poor prognosis in head-and-neck squamous cell carcinoma via regulating the epithelial-to-mesenchymal transition and chemosensitivity. Oral Oncol. 52:66–74. 2016. View Article : Google Scholar : PubMed/NCBI
4	Xia P and Xu XY: Epithelial-mesenchymal transition and gastric cancer stem cell. Tumour Biol. 39:10104283176983732017. View Article : Google Scholar : PubMed/NCBI
5	Kong FF, Qu ZQ, Yuan HH, Wang JY, Zhao M, Guo YH, Shi J, Gong XD, Zhu YL, Liu F, et al: Overexpression of FOXM1 is associated with EMT and is a predictor of poor prognosis in non-small cell lung cancer. Oncol Rep. 31:2660–2668. 2014. View Article : Google Scholar : PubMed/NCBI
6	Luo W, Fang W, Li S and Yao K: Aberrant expression of nuclear vimentin and related epithelial-mesenchymal transition markers in nasopharyngeal carcinoma. Int J Cancer. 131:1863–1873. 2012. View Article : Google Scholar : PubMed/NCBI
7	Naber HP, Drabsch Y, Snaar-Jagalska BE, ten Dijke P and van Laar T: Snail and Slug, key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion. Biochem Biophys Res Commun. 435:58–63. 2013. View Article : Google Scholar : PubMed/NCBI
8	Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, Winslow MM and Downward J: HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature. 505:212–217. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wu J and Wei JJ: HMGA2 and high-grade serous ovarian carcinoma. J Mol Med (Berl). 91:1155–1165. 2013. View Article : Google Scholar : PubMed/NCBI
10	Luo Y, Li W and Liao H: HMGA2 induces epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Oncol Lett. 5:1353–1356. 2013.PubMed/NCBI
11	Liu B, Pang B, Hou X, Fan H, Liang N, Zheng S, Feng B, Liu W, Guo H, Xu S, et al: Expression of high-mobility group AT-hook protein 2 and its prognostic significance in malignant gliomas. Hum Pathol. 45:1752–1758. 2014. View Article : Google Scholar : PubMed/NCBI
12	Langelotz C, Schmid P, Jakob C, Heider U, Wernecke KD, Possinger K and Sezer O: Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer. Br J Cancer. 88:1406–1410. 2003. View Article : Google Scholar : PubMed/NCBI
13	Wang X, Liu X, Li AY, Chen L, Lai L, Lin HH, Hu S, Yao L, Peng J, Loera S, et al: Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. Clin Cancer Res. 17:2570–2580. 2011. View Article : Google Scholar : PubMed/NCBI
14	Xi YN, Xin XY and Ye HM: Effects of HMGA2 on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Asian Pac J Trop Med. 7:289–292. 2014. View Article : Google Scholar : PubMed/NCBI
15	Zou Q, Wu H, Fu F, Yi W, Pei L and Zhou M: RKIP suppresses the proliferation and metastasis of breast cancer cell lines through up-regulation of miR-185 targeting HMGA2. Arch Biochem Biophys. 610:25–32. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zhao XP, Zhang H, Jiao JY, Tang DX, Wu YL and Pan CB: Overexpression of HMGA2 promotes tongue cancer metastasis through EMT pathway. J Transl Med. 14:262016. View Article : Google Scholar : PubMed/NCBI
17	Cai J, Shen G, Liu S and Meng Q: Downregulation of HMGA2 inhibits cellular proliferation and invasion, improves cellular apoptosis in prostate cancer. Tumour Biol. 37:699–707. 2016. View Article : Google Scholar : PubMed/NCBI
18	Sun J, Sun B, Zhu D, Zhao X, Zhang Y, Dong X, Che N, Li J, Liu F, Zhao N, et al: HMGA2 regulates CD44 expression to promote gastric cancer cell motility and sphere formation. Am J Cancer Res. 7:260–274. 2017.PubMed/NCBI
19	Dong J, Wang R, Ren G, Li X, Wang J, Sun Y, Liang J, Nie Y, Wu K, Feng B, et al: HMGA2-FOXL2 axis regulates metastases and epithelial-to-mesenchymal transition of chemoresistant gastric cancer. Clin Cancer Res. 23:3461–3473. 2017. View Article : Google Scholar : PubMed/NCBI
20	Wang H, Jiang Z, Chen H, Wu X, Xiang J and Peng J: MicroRNA-495 inhibits gastric cancer cell migration and invasion possibly via targeting high mobility group AT-hook 2 (HMGA2). Med Sci Monit. 23:640–648. 2017. View Article : Google Scholar : PubMed/NCBI
21	Liu Y, Fu QZ, Pu L, Meng QG, Liu XF, Dong SF, Yang JX and Lv GY: HMGA2 expression in renal carcinoma and its clinical significance. J Med Biochem. 34:338–343. 2015. View Article : Google Scholar : PubMed/NCBI
22	Na N, Si T, Huang Z, Miao B, Hong L, Li H and Qiu J and Qiu J: High expression of HMGA2 predicts poor survival in patients with clear cell renal cell carcinoma. Onco Targets Ther. 9:7199–7205. 2016. View Article : Google Scholar : PubMed/NCBI
23	Shi Z, Wu D, Tang R, Li X, Chen R, Xue S, Zhang C and Sun X: Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells. J Biosci. 41:229–236. 2016. View Article : Google Scholar : PubMed/NCBI
24	Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S, Chen P, Chen J, Chada KK, He C, et al: HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA. 110:pp. 9920–9925. 2013; View Article : Google Scholar : PubMed/NCBI
25	Natarajan S, Hombach-Klonisch S, Dröge P and Klonisch T: HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells. Neoplasia. 15:263–280. 2013. View Article : Google Scholar : PubMed/NCBI
26	Yang E, Cisowski J, Nguyen N, O'Callaghan K, Xu J, Agarwal A, Kuliopulos A and Covic L: Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2. Oncogene. 35:1529–1540. 2016. View Article : Google Scholar : PubMed/NCBI
27	Kaur H, Ali SZ, Huey L, Hütt-Cabezas M, Taylor I, Mao XG, Weingart M, Chu Q, Rodriguez FJ, Eberhart CG, et al: The transcriptional modulator HMGA2 promotes stemness and tumorigenicity in glioblastoma. Cancer Lett. 377:55–64. 2016. View Article : Google Scholar : PubMed/NCBI
28	Micalizzi DS, Haber DA and Maheswaran S: Cancer metastasis through the prism of epithelial-to-mesenchymal transition in circulating tumor cells. Mol Oncol. 11:770–780. 2017. View Article : Google Scholar : PubMed/NCBI
29	Xia YY, Yin L, Jiang N, Guo WJ, Tian H, Jiang XS, Wu J, Chen M, Wu JZ and He X: Downregulating HMGA2 attenuates epithelial-mesenchymal transition-induced invasion and migration in nasopharyngeal cancer cells. Biochem Biophys Res Commun. 463:357–363. 2015. View Article : Google Scholar : PubMed/NCBI
30	Li Y, Zhao Z, Xu C, Zhou Z, Zhu Z and You T: HMGA2 induces transcription factor Slug expression to promote epithelial-to-mesenchymal transition and contributes to colon cancer progression. Cancer Lett. 355:130–140. 2014. View Article : Google Scholar : PubMed/NCBI
31	Ke Z, Caiping S, Qing Z and Xiaojing W: Sonic hedgehog-Gli1 signals promote epithelial-mesenchymal transition in ovarian cancer by mediating PI3K/AKT pathway. Med Oncol. 32:3682015. View Article : Google Scholar : PubMed/NCBI
32	Qiao B, He BX, Cai JH, Tao Q and King-Yin Lam A: MicroRNA-27a-3p modulates the Wnt/β-catenin signaling pathway to promote epithelial-mesenchymal transition in oral squamous carcinoma stem cells by targeting SFRP1. Sci Rep. 7:446882017. View Article : Google Scholar : PubMed/NCBI
33	Xu F, Zhang J, Hu G, Liu L and Liang W: Hypoxia and TGF-β1 induced PLOD2 expression improve the migration and invasion of cervical cancer cells by promoting epithelial-to-mesenchymal transition (EMT) and focal adhesion formation. Cancer Cell Int. 17:542017. View Article : Google Scholar : PubMed/NCBI