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Evidence That APC Regulates Survivin Expression

A Possible Mechanism Contributing to the Stem Cell Origin of Colon Cancer

Division of Genetic and Preventive Medicine [T. Z., T. O., Zhe. G., Zhi. G., S. M. E., B. M. B.] and Kimmel Cancer Center [B. M. B.], Thomas Jefferson University, Philadelphia, PA 19107; CA^*TX Inc., Gladwyne, Pennsylvania 19035 [J. Z. F.]

Because colorectal cancers (CRCs) frequently display APC mutation, inhibition of apoptosis, and increased expression of the antiapoptotic protein survivin, we hypothesized that APC mutation inhibits apoptosis by allowing constitutive survivin expression. Using HT-29 CRC cell lines having inducible wild-type APC (wt-APC) or transfected dominant-negative TCF-4, we show that wt-APC down-regulates survivin expression via APC/ß-catenin/TCF-4 signaling. Using normal colonic epithelium, we found survivin by immunostaining/reverse transcription-PCR to be preferentially expressed in the lower crypt (which inversely correlates with wt-APC’s expression pattern). Thus, wt-APC, by progressively decreasing survivin and increasing apoptosis from crypt bottom to top, may limit the population size of stem cells and other proliferative cells in the lower crypt; mutant APC may allow expansion of these populations, thereby initiating tumorigenesis.

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