Aggressive
cancers and embryonic stem (ES) cells share a common gene expression signature. Identifying the key factors/pathway(s) within this ES signature responsible for the aggressiveness of
cancers can lead to a potential cure. In this study, we find that SALL4, a gene involved in the maintenance of ES cell self-renewal, is aberrantly expressed in 47.7% of primary human
endometrial cancer samples. It is not expressed in normal or hyperplastic endometrial. More importantly, SALL4 expression is positively correlated with worse patient survival and aggressive features such as
metastasis in
endometrial carcinoma. Further functional studies have shown that loss of SALL4 inhibits
endometrial cancer cell growth in vitro and tumorigenicity in vivo, as a result of inhibition of cell proliferation and increased apoptosis. In addition, downregulation of SALL4 significantly impedes the migration and invasion properties of
endometrial cancer cells in vitro and their metastatic potential in vivo. Furthermore, manipulation of SALL4 expression can affect drug sensitivity of
endometrial cancer cells to
carboplatin. Moreover, we show that SALL4 specifically binds to the c-Myc promoter region in
endometrial cancer cells. While downregulation of SALL4 leads to a decreased expression of c-Myc at both
protein and
mRNA levels, ectopic SALL4 overexpression causes increased c-Myc
protein and
mRNA expression, indicating that c-Myc is one of the SALL4 downstream targets in endometrial
tumorigenesis. In summary, we are the first to demonstrate that SALL4 has functional role(s) in
metastasis and drug resistance in aggressive
endometrial cancer. As a consequence of its functional roles in
cancer cell and absence in normal tissue, SALL4 is a potential novel therapeutic target for the high-risk
endometrial cancer patient population.