Abstract 3047: Stem cell factor SALL4 plays a critical role in maintaining cell survival in endometrial cancer

Abstract

Abstract Endometrial carcinoma is the most common gynecologic malignancy in the world. While most patients (85%) are surgically cured with a hysterectomy, unfortunately, the remaining 15% cases tend to have persistent or recurrent cancer that are resistant to current radiation and chemotherapy. Discovery of novel pathway(s) involved in the pathogenesis of the endometrial cancer can provide new therapeutic opportunities. The transcription factor SALL4 is required for early embryonic development and for the maintenance of human and murine embryonic stem cell (ESC) pluripotency. Our previous studies have shown that SALL4 also plays an essential role in leukemogenesis. We hypothesize that SALL4 may play a similar role in the pathogenesis of sold tumors. We initiated our study by surveying the expression of SALL4 in various solid tumors. We found that 50% of endometrial carcinoma patients had aberrant expression of SALL4 compared to that of normal tissue by immunohistochemistry staining (n=30). This finding was further validated by quantitative real-time PCR (N=8). In addition, we evaluated SALL4 expression in several endometrial cancer cell lines, such as poorly-differentiated cell line AN3CA, KLE, and moderately differentiated cell line, HEC-1A. Western blot showed that SALL4 was highly expressed in AN3CA and KLE, but not detectable in HEC-1A cells. To test whether SALL4 plays a functional role in this disease, we chose to use loss-of-function approach. Knock-down of SALL4 in AN3CA and KLE was achieved by SALL4 specific shRNA. On day 5 after infection, down-regulation of SALL4 induced a high degree of cell death (50%). MTT proliferation assay also confirmed cell growth rate was significantly decreased compared to that from scramble control. We further investigated whether this decreased viable cells was due to apoptosis or cell cycle arrest or both. Western blot showed that knock-down of SALL4 could induce caspase-dependent apoptosis, as evidenced by detection of more caspase 3 cleavage products compared to that of scramble control. In addition, BrdU cell cycle assay showed that knock-down of SALL4 led to decreased S phase along with G2 arrest. Using ChIP-on-chip assay, we have found that SALL4 could bind to c-MYC promoter region. Consistently, our western blot show c-MYC was dramatically decreased after SALL4 knocking down in AN3CA cells compared to scramble control. In summary, for the first time our data show that SALL4 is aberrantly expressed both in primary endometrial carcinoma and poorly differentiated endometrial cell lines. Loss-of -function study demonstrated that SALL4 play an essential role in cell survival in endometrial carcinoma by activating c-MYC pathway. Further study will reveal whether SALL4 can be used as a novel therapeutic target for those advanced, progressive or recurrent endometrial carcinoma. 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 3047. doi:10.1158/1538-7445.AM2011-3047