C10ORF97 is a novel tumor-suppressor gene of non-small-cell lung cancer and a functional variant of this gene increases the risk of non-small-cell lung cancer

Abstract

In an earlier study we showed that C10ORF97 (chromosome-10, open reading frame-97) was expressed in almost all of the tissues and cell lines tested, and that it inhibited the growth of seven tumor cell lines, including two lung carcinoma cell lines (A549 and PG). Here, we show that C10ORF97 is downregulated in non-small-cell lung cancer (NSCLC) tissue compared with normal lung tissue. Overexpression of C10ORF97 significantly suppressed human lung carcinoma A549 cell growth (proliferation and anchorage-independent growth in soft agar) and motility (migration and adhesion). This tumor-suppressive function of C10ORF97 was also verified in vivo. We further found that C10ORF97 caused G 1 arrest of A549 cells and modulated the expression level of several cell-cycle regulators (such as CDK2, cyclin-E and p27). These effects of C10ORF97 were mediated by physical association between C10ORF97 and Jun-activating domain-binding protein-1 (JAB1), and blocking of JAB1-mediated translocation of p27 from the nucleus to the cytoplasm. Together, these results indicated that C10ORF97 functions as a novel tumor suppressor by modulating several key G 1 /S-regulatory proteins by interacting with JAB1. These findings led us to hypothesize that a single-nucleotide polymorphism (SNP) in the C10ORF97 gene that affects its expression might be associated with susceptibility to NSCLC. SNP216 C4T (rs2297882) in the C10ORF97 Kozak sequence was identified, and allele T of SNP216 suppressed C10ORF97 expression in vitro and in vivo. Furthermore, the TT genotype of SNP216 was associated with an increased risk of NSCLC (adjusted odds ratio ¼ 1.73 (95% confidence interval: 1.33-2.25), P ¼ 4.6 Â 10 -5). These data indicated that C10ORF97 is a tumor suppressor of NSCLC progression and C10ORF97-SNP216 may serve as a predictor of NSCLC.

CARP Is a Potential Tumor Suppressor in Gastric Carcinoma and a Single-Nucleotide Polymorphism in CARP Gene Might Increase the Risk of Gastric Carcinoma

“…Recently, we have pointed out that the expression of CARP is significantly decreased in lung cancer tissues, suggesting that decreased expression of CARP might be associated with tumorigenesis of lung cancer [10]. In the present study, a similar tendency in the change of CARP expression was observed in gastric carcinoma tissue.…”

“…It has been reported that JAB1 promotes cell proliferation by directly binding to p27, and induces nuclear export and subsequent degradation of p27 [27], [28]. We have demonstrated that CARP repressed JAB1-mediated AP-1 activation and enhanced p27 nuclei accumulation [10]. JAB1 induces p53 cytoplasmic localization and its subsequent degradation, which helps to maintain low levels of p53 under normal conditions [26], [29], [30].…”

“…The rs2297882 is located in the Kozak sequence of CARP gene, and it has been demonstrated to cause a decrease in CARP gene transcription/translation in lung cancer [10]. In the present study, the rs2297882 of BGC-823 cells is identified by DNA sequencing, and the genotype of rs2297882 is TC.…”

“…Studies on the biological function of CARP have proved that overexpression of CARP could significantly promote apoptosis in lung carcinoma A549 and human embryonic kidney HEK293s cells, and inhibit cell proliferation in lung carcinoma A549 and PG, melanoma WM451, prostate cancer PC-3 and PC-3M, liver cancer H7402, and bladder cancer BIU87 cells [9], suggesting that CARP is a pro-apoptotic protein and has potential anti-tumor effects. In our previous study, we detected that CARP was downregulated in non-small-cell lung cancer (NSCLC) tissue, and CAPR suppressed cell growth and motility in human lung carcinoma A549 cells by modulating several key G1/S-regulatory proteins [10]. Emerging evidence indicates the tumor-suppressive function of CARP in the development of tumors.…”

“…In the current study, we initially observed that the expression of CARP was similarly downregulated in gastric carcinoma tissue by cDNA array and tissue microarray analysis methods. Based on the results that SNP216C>T (rs2297882) in the CARP gene was related to susceptibility to NSCLC [10], we genotyped rs2297882 and analyzed the frequency difference between stomach cancer patients and matched controls. The results showed that the frequency of the rs2297882 TT genotype was significantly higher in the gastric carcinoma patients, and that the allele T of SNP216 was associated with the low expression levels of CARP and the increased risk of stomach cancer.…”