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J. Biol. Chem., Vol. 278, Issue 47, 46278-46287, November 21, 2003

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Oncogenic Ki-Ras Inhibits the Expression of Interferon-responsive Genes through Inhibition of STAT1 and STAT2 Expression^*

Lidija Klampfer, Jie Huang, Georgia Corner, John Mariadason, Diego Arango, Takehiko Sasazuki, Senji Shirasawa, and Leonard Augenlicht

From the Albert Einstein Cancer Center, Montefiore Medical Center, Department of Oncology, Bronx, New York 10467 and the Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan

Endogenous interferon (IFN) promotes the host response to primary tumors, and IFN-insensitive tumors display increased tumorigenicity and can evade tumor surveillance mechanisms. Here we demonstrate that activating mutations of Ki-ras are sufficient to inhibit the expression of STAT1 and STAT2, transcription factors required for signaling by IFNs, providing a potential mechanism for the insensitivity of tumors to IFNs. We demonstrated that colon cancer cell lines with Ki-ras mutations display reduced expression of IFN-responsive genes compared with the cell lines that have retained wild type Ras and that inactivation of the mutant Ki-ras allele in the HCT116 colon cancer cell line is sufficient to restore the expression of STAT1, STAT2, and IRF-9. Accordingly, the expression of 27 interferon-inducible genes was reduced in HCT116 cells compared with the isogenic clones with targeted deletion of the mutant Ki-ras allele, Hkh2 and Hke-3. The expression of IFN receptors did not differ among the isogenic cell lines. IFN stimulated transcription of a STAT1-dependent reporter gene was impaired by RasV12, demonstrating a transmodulation of IFN/STAT signaling by activated Ras. Finally, we demonstrated that the expression of RasV12 in 293T cells is sufficient to inhibit the endogenous expression of STAT1 and STAT2, confirming the negative regulation of IFN signaling by oncogenic Ras. Our data demonstrate that the signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons. Furthermore, the data suggest that tumors harboring activating Ki-ras mutations may escape tumor surveillance mechanisms due to reduced responsiveness to IFN.

Received for publication, May 6, 2003 , and in revised form, August 27, 2003.

^* This work was supported by a Montefiore Medical Center New Research Initiative Award (to L. K.), American Cancer Society Institutional Research Grant ACS IRG 98-274-01 (to L. K.), National Institutes of Health Grant UO1 CA88104 (to L. A.), and Cancer Center Grant P30-13330. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Albert Einstein Cancer Center, Montefiore Medical Center, 111 E 210th St., Bronx, NY 10467. Tel.: 718-920-6579; Fax: 718-882-4464; E-mail: lklampf{at}aecom.yu.edu.

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