Neoplastic progression in human tissues appears to be paralleled by a series of genetic and epigenetic alterations. In human colorectal cancers, defect Wnt/␤-catenin/T-cell factor and RAS/RAF signaling pathways have a major contributing role in tumor initiation and progression. To date, much of the research on the consequences of ␤-catenin activation has been focused on genes whose expression is believed to be activated by ␤-catenin-associated T-cell factor-dependent transcription. Little is known about genes whose expression may be down-regulated secondary to ␤-catenin activation. Using a subtractive suppression hybridization approach, we identified a gene with markedly decreased expression in rat RK3E epithelial cells neoplastically transformed by ␤-catenin. Because expression of this gene was also down-regulated in RK3E transformed by several other oncogenes, the gene was named DRO1 for "down-regulated by oncogenes 1." Compared with corresponding normal tissues, DRO1 expression was found to be very reduced in colon and pancreatic cancer cell lines as well as in most colorectal cancer specimens. The predicted DRO1 protein contains three repetitive elements with significant similarity to the carboxyl-terminal regions of the predicted proteins from DRS/SRPX/ ETX1 and SRPUL genes, suggesting the existence of a new protein family. Ectopic expression of DRO1 in neoplastically transformed RK3E or colorectal and pancreatic cancer cell lines lacking endogenous DRO1 expression resulted in substantial inhibition of growth properties. DRO1 was found to suppress anchorage independent growth and to sensitize cells to anoikis and CD95-induced apoptosis. Our findings suggest that inhibition of DRO1 expression may be an important event in the development of colorectal and pancreatic cancers.

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IFN-A is commonly used for biotherapy of neuroendocrine carcinomas. However, its antitumor efficacy is often limited due to IFN resistance. In this study, we evaluate the role of suppressor of cytokine signaling protein 1 (SOCS1) in modulating the effects of type I IFNs (IFN-A and IFN-B) in human neuroendocrine BON1 and CM tumor cells. In both cell lines, type I IFNs activated signal transducers and activators of transcription (STAT) and significantly decreased cell viability. However, the effects of IFN-B were significantly more pronounced than those of IFN-A and involved the induction of the intrinsic apoptotic pathway as shown by cleavage of caspase-8, Bid, and caspase-9. Stable overexpression of SOCS1 completely abolished the apoptotic effects of both type I IFNs. In contrast, small interfering RNA (siRNA)-mediated silencing of SOCS1 resulted in strongly enhanced type I IFN signaling as shown by increased and prolonged STAT phosphorylation and stronger induction of apoptosis. Silencing of SOCS1 was associated with down-regulation of basal Bcl-2 and Bcl-xL and up-regulation of basal Bak and Bax, suggesting that reduced SOCS1 expression might lower the threshold of susceptibility to type I IFN-mediated apoptosis by decreasing the ratio of antiapoptotic to proapoptotic molecules. In summary, our results indicate an important role of SOCS1 in IFN resistance of neuroendocrine tumor cells, mediated through negative regulation of type I IFN-induced Jak/STAT signaling. Knocking down SOCS1 by siRNA is a promising new approach to enhance the therapeutic potency of type I IFNs in neuroendocrine tumors. [Cancer Res 2007;67(10):5025-32]

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