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Tumor Surveillance Monitoring Prostate Tumorigenesis
Prostate cancer (PC) progresses from intra-epithelial neoplasia, or de novo, locally-invasive carcinoma, to metastatic cancer that advances to hormone refractory prostate cancers. The molecular events driving prostate tumorigenesis in general include activation of oncogenic activities and inactivation of tumor suppression activities. A thorough understanding of these molecular events is the key for prevention, diagnosis, and therapy of PC, and intensive research efforts are being devoted to elucidate the critical molecular events that drive prostate cancer progression. A key step among these events, to which our current knowledge is very limited, is how PC progression is prevented.
A recent report by Xie et al. added to our understanding of the mechanisms that guard against PC progression, tumor surveillance of prostate cancer progression. By the examination of a set of PC cell lines, which in general represent the process of PC progression including non-tumorigenic prostate epithelial BPH cells, androgen-dependent LNCaP PC cells, and androgen-independent DU145 and PC3 cells, the authors demonstrated a robust increase of IQGAP2 from BPH to LNCaP cells. Interestingly, this was followed by an impressive decrease of IQGAP2 from LNCaP to androgen-independent DU145 and PC3 cells. More importantly, this bio-phase change in IQGAP2 protein expression was also observed in their study of 53 PC patients, i.e., up-regulation of IQGAP2 from apparently normal prostate gland epithelial cells to PIN lesions and carcinomas of low grade (primary Gleason score 3) and down regulation of IQGAP2 in carcinomas of Gleason 4 or 5. Additionally, in their study of PC cells, it was found that high levels of IQGAP2 inhibit cell proliferation. Taken together, Xie et al. proposed that the early phase of increase in IQGAP2 is a defense or a surveillance mechanism aimed to prevent PC progression and that the later phase of IQGAP2 reduction allows PC progression. Therefore, IQGAP2 may be a PC surveillance type of tumor suppressor.[1]
The authors finding is consistent with recent reports that high levels of IQGAP2 mRNA were detected in local and non-metastatic prostate carcinomas,[2] and low levels of IQGAP2 mRNA were reported in hormone refractory prostate cancer.[3] IQGAP2 was reported to suppress the tumorigenesis of liver and gastric cancer.[4,5]
While the tumor surveillance type of tumor suppressor, largely p14ARF, has been well studied for many years in other types of human cancer,[6] tumor surveillance function in suppressing prostate tumorigenesis has not been clearly investigated. Therefore, the research performed by Xie et al. was a first step in the elucidation of tumor surveillance function in PC. The understanding of tumor surveillance has its clinical values. The two-phase expression pattern can be used as a diagnostic marker for early and advanced prostate carcinoma. It will also be interesting to see whether preventing reduction of IQGAP2 may play a role in reducing PC progression.
Although Xie et al. provided a clear indication that IQGAP2 provides a surveillance mechanism to prevent PC progression, further research is needed to consolidate the concept. What are the primary oncogenic activities during prostate tumorigenesis that is monitored by IQGAP2? How does oncogenic activity upregulate IQGAP2? What are the mechanisms responsible for IQGAP2 downregulation when PC progresses?
References
- Xie Y, Yan J, Cutz JC, Rybak AP, He L, Wei F, Kapoor A, Schmidt VA, Tao L, Tang D. IQGAP2, A candidate tumour suppressor of prostate tumorigenesis. Biochim Biophys Acta. 1822:875-84, 2012.
- Lozano JJ, Soler M, Bermudo R, Abia D, Fernandez PL, Thomson TM, Ortiz AR. Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data. BMC Genomics 6:109, 2005.
- Tamura K, Makino A, Hullin-Matsuda F, Kobayashi T, Furihata M, Chung S, Ashida S, Miki T, Fujioka T, Shuin T, Nakamura Y, Nakagawa H. Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism. Cancer Res. 69:8133-40, 2009.
- Jin SH, Akiyama Y, Fukamachi H, Yanagihara K, Akashi T, Yuasa Y. IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells. Int J Cancer 122:1040-6, 2008.
- Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12:2984-91, 1998.
- White CD, Khurana H, Gnatenko DV, Li Z, Odze RD, Sacks DB, Schmidt VA. IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma. BMC Gastroenterol. 10:125, 2010.
Written by:
Damu Tang, PhD* as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
*Associate Professor
Department of Medicine
McMaster University
Hamilton, ON
Canada
IQGAP2, A candidate tumour suppressor of prostate tumorigenesis - Abstract
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