In this report we describe the unexpected discovery of aberrant HIP1 expression in human prostate and colon cancer. We also provide data showing that HIP1 is necessary for cellular survival. This is consistent with HIP1 overexpression in human cancer cell lines and tissues, as its maintenance of survival could provide a selective growth advantage to cancer cells. However, both results described here contrast with a report that shows that HIP1 promotes apoptosis in a caspase-8–independent fashion (26
) and another study that reports that HIP1 causes apoptosis in a caspase-8–dependent fashion (27
). The primary reason for the discrepancy may be that these two previous reports use a different HIP1 cDNA. This cDNA lacks an N-terminal sequence that we have recently identified (9
). It is not clear whether this difference is due to the existence of alternative splice forms of HIP1 mRNA. We speculate that the cDNA used in the previous reports is functionally similar to the dominant negative mutant HIP1/ΔE described herein. Similar to our results with HIP1, the N-terminus of the yeast ortholog of HIP1, Sla2p
, has been shown to be necessary for survival (4
). Thus, the N-terminus of these proteins, containing the ENTH domain, may be critical in mediating their role(s) in cellular survival or death pathways.
We found that expression of HIP1 in human prostate tumors had a significant association with prostate cancer progression. This was evidenced by a lack of expression in the benign epithelium, intermediate expression levels in precancerous prostate lesions (high-grade PIN), and high frequency of expression in metastatic prostate cancer. In addition, progression after prostatectomy did not occur in any of the 14 prostate cancer cases that lacked HIP1 expression, suggesting that HIP1 may distinguish aggressive prostate cancers from those with a more indolent clinical course.
It is intriguing to speculate that, similar to HIP1 expression in prostate cancer, the stratification of colonic adenocarcinomas based on HIP1 expression may have independent predictive value with regard to both tumor aggressiveness and patient survival. Because the vast majority of colonic tumors produce a similar histologic picture, it is difficult to obtain prognostic information from routine histologic analysis. Therefore, it will be of considerable interest to correlate clinical outcomes from a large cohort of patients with colon cancer with tumor HIP1 expression. If expression does correlate with reduced survival, as is true for prostate cancer, this single molecular marker may be one of the most useful clinical tools for prognostication in the care of patients with two of the most common forms of cancer.
The likelihood of a contributory role for HIP1 in the development of cancer is strengthened by its overexpression in prostate cancers of the TRAMP mouse and data suggesting that wild-type HIP1 expression maintains cell survival. However, it remains possible that HIP1 overexpression, although specific to prostate and colon cancer, is a consequence of tumor formation. We are working to determine whether HIP1 expression is causal by using HIP1 transgenic and knockout mice to discover whether expression of HIP1 is sufficient for formation of tumors in vivo.
Finally, the implications of HIP1 expression in cancer progression are exciting. As a factor necessary for cellular survival, HIP1 overexpression in cancer may reduce the growth factor dependence of cancer cells by dysregulating cell surface growth factor receptor density or growth factor secretion, as a consequence of its role in clathrin-mediated trafficking. By reducing dependence on growth factors, cancer cells can gain a proliferative advantage, which could allow for additional mutations to accumulate in surviving cells. If HIP1 proves to be necessary for cellular transformation, HIP1 function in clathrin trafficking may provide a novel pathway for design of anticancer drugs.