Abstract 606: Expression and role of high mobility group protein AT-hook 1 (HMGA1) in human renal cell carcinoma

Abstract

Abstract Even though molecular targeted therapy has improved the clinical outcome of metastatic renal cell carcinoma (mRCC) patients, complete response is rarely observed. Identification of molecules possessing significant molecular functions in mRCC is mandatory for developing new therapeutic modalities for mRCC. High mobility group protein AT-hook 1 (HMGA1) is overexpressed in many types of cancer cells, but is not or at very low levels expressed in normal adult tissues. Expression of HMGA1 has been reported to be associated with metastatic potential and progression of cancer. We have reported that transfection of HMGA1 into prostate cancer cell lines induces chromosomal rearrangement (Cancer Res, 2002) and expression of matrix metalloproteinase 2 (Prostate, 2004) suggesting that HMGA1 may play an important role in the progression of prostate cancer. In this study, we examined expression and function of HMGA1 in human renal cell carcinoma (RCC). Expression of HMGA1 in six human RCC cell lines, Caki-1, ACHN, NC 65, RCC-4, 786-O, and A498, was examined by immunoblot and immunohistochemistry. The expression level of HMGA1 detected by immunoblot was Caki-1=ACHN>NC65>786-O, while RCC-4 and A498 barely expressed HMGA1. Immunohistochemistry showed nuclear localization of HMGA1 in these cell lines. Expression of HMGA1 in renal tumor tissue and normal kidney tissue from the same patients who underwent radical nephrectomy was examined by immunoblot. Immunoblot of surgical samples of 41 cases of RCC revealed that HMGA1 is not expressed in normal kidney tissues from all the cases. On the other hand, immunoblot showed that expression of HMGA1 was observed in 1 out of 23 (4%) non-metastatic cases (M0) compared to 6 out of 18 (33%) metastatic cases (M1) (P=0.031), and 3 out of 29 (10%) G1-2 cases compared to 4 out of 9 (44%) G3 cases (P=0.041). Colony formation assay and flowcytometry were performed using Caki-1 after transfecting with siRNA to knock down HMGA1. Knock-down of HMGA1 expression in Caki-1 cells by siRNA remarkably suppressed colony formation (control siRNA 86.0±5.3 vs HMGA1 siRNA 7.3±1.5, P<0.001)and also induced apoptosis associated with increased subG1 fraction (control siRNA 1.9% vs HMGA1 siRNA 34.6%). These findings suggest that HMGA1 might be correlated with histological grade and metastatic potential of RCC associated with enhanced anti-apoptotic mechanism. No expression in normal kidney tissues, preferential expression in renal tumor tissues of metastatic cases, and remarkable suppression of colony formation by siRNA suggest that HMGA1 might be a potential target molecule for novel therapeutic modalities of mRCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 606. doi:10.1158/1538-7445.AM2011-606