Abstract OPS01-02: Inflammation and cancer: Interweaving microRNA, innate immune, and p53 pathways
Authors: Harris Curtis C. 
Published: January 2011

Abstract
Infection and chronic inflammation contribute to the etiology and pathogenesis of about one in four of all cancer cases. Mediators of the inflammatory response, e.g., cytokines, free radicals, prostaglandins, non-coding RNAs, and growth factors, can induce genetic and epigenetic changes including point mutations in tumor suppressor genes, DNA methylation and posttranslation modifications, causing alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (1-6). IL-6 and IL-8 cooperate with microRNA in the induction of cellular senescence in benign tumors (7-9) and as autocrine growth factors in carcinoma (10-14).
Cellular senescence is also a tumor suppressor mechanism of p53 (15,16). We are studying the molecular mechanisms of cellular senescence in normal and malignant human cells and the role of the telomeric multiprotein complex, shelterin, that includes TRF2 and POT1. Our ongoing studies have revealed that p53 and its endogenous isoforms regulate both specific microRNAs and TRF2 expression as mechanisms of replicative senescence. In addition, POT1 isoforms are functionally diverse in both maintaining telomeric integrity and preventing p53-dependent senescence induced by telomeric shortening (17,18). A switch in the expression patterns of p53 isoforms 133Np53 and p53 beta can cause cellular senescence in vitro and is also associated with the transition of benign to malignant human colon tumors in vivo (19).
Expression of microRNAs and inflammatory genes are biomarkers of cancer risk, diagnosis, prognosis, and therapeutic outcome. We are especially interested in the interaction of the innate immune pathway with environmental tobacco smoking in lung cancer risk (20) and the interaction of inflammatory cytokines, p53 isoforms, and microRNAs as prognostic classifiers of early stage lung and colon cancer and their functional role in the development of micrometastases [reviewed in (3)] (21-25).
References:
1. Tlsty TD and Coussens LM: Tumor stroma and regulation of cancer development. Annu Rev Pathol, 1:119-150, 2006.
2. Croce CM: Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet, 10:704-714, 2009.
3. Schetter AJ, Heegaard NH, and Harris CC: Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 31:37-49, 2010.
4. Hussain SP, Hofseth LJ, and Harris CC: Radical causes of cancer. Nat Rev Cancer, 3:276-285, 2003.
5. Coppe JP, Desprez PY, Krtolica A, and Campisi J: The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol, 5:99-118, 2010.
6. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, and Campisi J: Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol, 11:973-979, 2009.
7. Kuilman T, Michaloglou C,Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, and Peeper DS: Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 133:1019-1031, 2008.
8. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda dF, Bernard D, Hernando E, and Gil J: Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell, 133:1006-1018, 2008.
9. Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, Lithgow GJ, and Campisi J: MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY), 1:402-411, 2009.
10. Lazar-Molnar E, Hegyesi H, Toth S, and Falus A: Autocrine and paracrine regulation by cytokines and growth factors in melanoma. Cytokine, 12:547-554, 2000.
11. Singh RK, Gutman M, Radinsky R, Bucana CD, and Fidler IJ: Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res, 54:3242-3247, 1994.
12. Zhu YM, Webster SJ, Flower D, and Woll PJ: Interleukin-8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer, 91:1970-1976, 2004.
13. Ancrile B, Lim KH, and Counter CM: Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev, 21:1714-1719, 2007.
14. Sparmann A and Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell, 6:447-458, 2004.
15. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, and Jacks T: Restoration of p53 function leads to tumour regression in vivo. Nature, 445:661-665, 2007.
16. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, and Lowe SW: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445:656-660, 2007.
17. Yang Q, Zhang R, Horikawa I, Fujita K, Afshar Y, Kokko A, Laiho P, Aaltonen LA, and Harris CC: Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. Cancer Res, 67:11677-11686, 2007.
18. Yang Q, Zheng YL, and Harris CC: POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol, 25:1070-1080, 2005.
19. Fujita K, Mondal AM, Horikawa I, Nguyen GH, Kumamoto K, Sohn JJ, Bowman ED, Mathe EA, Schetter AJ, Pine SR, Ji H, Vojtesek B, Bourdon JC, Lane DP, and Harris CC: p53 isoforms Delta133p53 and p53beta are endogenous regulators of replicative cellular senescence. Nat Cell Biol, 11:1135-1142, 2009.
20. Olivo-Marston SE, Yang P, Mechanic LE, Bowman ED, Pine SR, Loffredo CA, Alberg AJ, Caporaso N, Shields PG, Chanock S,Wu Y, Jiang R, Cunningham J, Jen J, and Harris CC: Childhood exposure to secondhand smoke and functional mannose binding lectin polymorphisms are associated with increased lung cancer risk. Cancer Epidemiol Biomarkers Prev, 18:3375-3383, 2009.
21. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J,Tanaka T, Calin GA, Liu CG, Croce CM, and Harris CC: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell, 9:189-198, 2006.
22. Seike M, Yanaihara N, Bowman ED, Zanetti KA, Budhu A, Kumamoto K, Mechanic LE, Matsumoto S, Yokota J, Shibata T, Sugimura H, Gemma A, Kudoh S,Wang XW, and Harris CC: A cytokine gene signature of the lung adenocarcinoma and its tissue environment predicts prognosis. J Natl Cancer Inst, 99:1257-1269, 2007.
23. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, and Harris CC: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA, 299:425-436, 2008.
24. Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, Mathe EA, Jen J,Yang P, Sugimura H, Gemma A, Kudoh S, Croce CM, and Harris CC: MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci U S A, 106:12085-12090, 2009.
25. Schetter AJ, Nguyen GH, Bowman ED, Mathe EA, Yuen ST, Hawkes JE, Croce CM, Leung SY, and Harris CC: Association of inflammation-related and microRNA gene expression with cancer-specific mortality of colon adenocarcinoma. Clin Cancer Res, 15:5878-5887, 2009.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):OPS01-02.