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.
Oncol Rep. 2018 Jan;39(1):101-108. doi: 10.3892/or.2017.6091. Epub 2017 Nov 10.
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.
高迁移率族 AT 钩 2（HMGA2）是高迁移率族家族的成员，已被报道与癌症进展相关。然而，尚无关于 HMGA2 与肾细胞癌转移之间的相关性的报道。在本研究中，我们发现与正常肾小管上皮 HK2 细胞系相比，HMGA2 在五种肾细胞癌细胞系中高度表达。此外，HMGA2 促进了肾细胞癌细胞的迁移和侵袭，划痕愈合和 Transwell 实验证实了这一点。随后，我们的结果表明，HMGA2 耗尽的 ACHN 细胞中 E-钙黏蛋白水平上调，而 N-钙黏蛋白、Twist1 和 Twist2 的表达下调。相反，HMGA2 在 786-O 细胞中的过表达增强了上皮-间充质转化（EMT）。此外，对数据库 Cancer Browser 的分析进一步验证了 HMGA2 与肾细胞癌中 Twist1 或 Twist2 的正相关。同时，Kaplan-Meier 分析表明，HMGA2 低表达与肾细胞癌患者总生存率的提高密切相关。为了证实 HMGA2 调节 EMT 的潜在机制，我们的结果表明，沉默 HMGA2 下调了 TGF-β 和 Smad2 的 mRNA 和蛋白水平，而 HMGA2 的过表达则产生相反的效果。此外，TGF-β 的过表达可以部分逆转 HMGA2 缺失引起的抗转移作用和间充质-上皮转化（MET），而 TGF-β 的缺乏则阻碍了由 HMGA2 过表达引起的促转移表型和 EMT 标志物的高表达。总之，我们的研究结果表明，HMGA2 通过 TGF-β 依赖性途径促进了肾细胞癌细胞的转移表型和 EMT 过程。此外，这些数据强烈表明，HMGA2 将来可能成为治疗肾细胞癌的潜在靶点和预后生物标志物。
