Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation

Abstract

Abstract. Cancer upregulated gene (CUG) 2, as a novel oncogene, has been predominantly detected in various cancer tissues, such as ovary, liver, lung and colon. We recently showed that CUG2 elevates STAT1 activity, leading to resistance to infection by oncolytic vesicular stomatitis virus. To investigate a possible role for CUG2-induced activation of STAT1 in oncogenesis, we first established a colon cancer cell line stably expressing CUG2 (Colon26L5-CUG2). Colon26L5-CUG2 exhibited higher levels not only in phosphorylation of STAT1, but also phosphorylation of Jak1/Tyk2 compared to that of the control (Colon26L5-Vec) cell line. Inhibition of Akt or ERK activity reduced phosphorylation of STAT1 in Colon26L5-CUG2 cells whereas inhibition of p38 MAPK did not significantly decrease levels of STAT1 phosphorylation, indicating that cell proliferation signals may be involved in CUG2-mediated activation of STAT1. Suppression of STAT1 expression diminished cell migration and wound healing compared to the control cells. In addition, since CUG2 expression conferred resistance to DNA damage caused by doxorubicin treatment, we investigated whether STAT1 is involved in resistance to doxorubicininduced cell death. We found that STAT1 was not activated in Colon26L5-Vec cells while phosphorylated STAT1 was maintained in Colon26L5-CUG2 cells during doxorubicin treatment. Furthermore, suppression of STAT1 expression sensitized Colon26L5-CUG2 cells to doxorubicin-induced apoptosis whereas the control cells exhibited resistance to doxorubicin. Taken together, our results suggest that CUG2 enhances metastasis and drug resistance through STAT1 activation, which eventually contributes to tumor progression. IntroductionTo discover new genes that play a crucial role in common tumorigenesis regardless of tissue origin, we analyzed commonly upregulated unknown genes in 242 normal and 300 tumor samples originating from 11 different tissues using the Affymetrix gene chip system. An Affymetrix fragment, later named cancer upregulated gene (CUG) 2 was identified as a candidate gene that is commonly upregulated in various tumor tissues such as ovary, liver, lung and colon. This CUG2 was mapped to chromosome 6q22.32; it spans ~8.5 kb with a three-exon structure and encodes a 88-amino acid polypeptide (1). Further study has revealed that CUG2 is a new component of centromere required for a proper kinetochore function during cell division (2). Of interest, CUG2 has been shown to harbor an oncogenic effect in a transplanted model using NIH3T3 cells expressing CUG2, in a manner similar to Ras (1). Although CUG2 overexpression leads to activated Ras and MAPKs including p38 MAPK, which eventually facilitates oncolytic reoviral replication (3), CUG2 contrastingly provides resistance to oncolytic vesicular stomatitis virus infection through activation of STAT1 as shown in our recent study (4).Although STAT1 is well known as a master transcription factor for IFN-related intracellular signaling, leading to antiviral activity, several lines of evidence hav...

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