Activation of the mTORC1 and STAT3 pathways promotes the malignant transformation of colitis in mice

He,Zhen; He,Xiaosheng; Chen,Zexian; Ke,Jia; He,Xiaowen; Yuan,Ruixue; Cai,Zerong; Chen,Xiuting; Wu,Xiaojian; Lan,Ping

doi:10.3892/or.2014.3421

Activation of the mTORC1 and STAT3 pathways promotes the malignant transformation of colitis in mice

Authors:
- Zhen He
- Xiaosheng He
- Zexian Chen
- Jia Ke
- Xiaowen He
- Ruixue Yuan
- Zerong Cai
- Xiuting Chen
- Xiaojian Wu
- Ping Lan
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Affiliations: Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China, Gastrointestinal Institute, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
Published online on: August 20, 2014 https://doi.org/10.3892/or.2014.3421
Pages: 1873-1880

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Abstract

Chronic inflammation is an underlying risk factor for colorectal cancer. No direct evidence has proven that inflammation in the colon promotes carcinogenesis. STAT3 plays an important role in the development of colitis-associated colorectal cancer (CAC). There is crosstalk between the mammalian target of rapamycin complex 1 (mTORC1) and the STAT3 pathways. The aim of the present study was to confirm that colitis promotes CAC and if so, to explore the function of the STAT3 and mTORC1 pathways in CAC. C57BL/6 mice were treated with axozymethane (AOM) and dextran sulfate sodium (DSS) to induce CAC. By varying the concentration of DSS (0, 1 and 2% respectively), we mimicked the CAC model with different degrees of inflammation and determined the risk of carcinogenesis. Expression of the STAT3 and mTORC1 pathways was detected. Finally, rapamycin, an mTORC1 inhibitor, was used to treat the CAC model. Tumor load, protein and gene expression of chemokines were determined. The multiplicity and tumor load of the high inflammation group were higher than those of the low inflammation group. Immunohistochemical staining and western blot analysis revealed that activation of the STAT3 and mTORC1 pathways increased gradually in the inflammation tissues and tumors. When we treated the mice with rapamycin, the tumor incidence, multiplicity and tumor load decreased. In addition, rapamycin widely suppressed the expression of pro‑inflammatory and anti-inflammatory chemokines in the tissues, including tumor necrosis factor-α, interferon-γ, IL-6, IL-10 and IL-12α. In conclusion, inflammation promotes the development of CAC via the STAT3 and mTORC1 pathways, which may be a viable treatment strategy for the chemoprevention of CAC.

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1	Balkwill F and Mantovani A: Inflammation and cancer: back to Virchow? Lancet. 357:539–545. 2001. View Article : Google Scholar : PubMed/NCBI
2	Eaden JA, Abrams KR and Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 48:526–535. 2001. View Article : Google Scholar : PubMed/NCBI
3	Gillen CD, Walmsley RS, Prior P, Andrews HA and Allan RN: Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut. 35:1590–1592. 1994.
4	Saleh M and Trinchieri G: Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol. 11:9–20. 2011. View Article : Google Scholar
5	Rhodes JM: Unifying hypothesis for inflammatory bowel disease and associated colon cancer: sticking the pieces together with sugar. Lancet. 347:40–44. 1996. View Article : Google Scholar : PubMed/NCBI
6	Rutter M, Saunders B, Wilkinson K, et al: Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 126:451–459. 2004. View Article : Google Scholar : PubMed/NCBI
7	Strimpakos AS, Karapanagiotou EM, Saif MW and Syrigos KN: The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev. 35:148–159. 2009. View Article : Google Scholar : PubMed/NCBI
8	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007. View Article : Google Scholar
9	Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar
10	Delgoffe GM and Powell JD: mTOR: taking cues from the immune microenvironment. Immunology. 127:459–465. 2009. View Article : Google Scholar : PubMed/NCBI
11	Magnuson B, Ekim B and Fingar DC: Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 441:1–21. 2012. View Article : Google Scholar : PubMed/NCBI
12	Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD and Pearson RB: Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors. 25:209–226. 2007. View Article : Google Scholar : PubMed/NCBI
13	Duvel K, Yecies JL, Menon S, et al: Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 39:171–183. 2010. View Article : Google Scholar : PubMed/NCBI
14	Guertin DA and Sabatini DM: An expanding role for mTOR in cancer. Trends Mol Med. 11:353–361. 2005. View Article : Google Scholar : PubMed/NCBI
15	Sarbassov DD, Ali SM, Sengupta S, et al: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 22:159–168. 2006. View Article : Google Scholar : PubMed/NCBI
16	Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI
17	Thiem S, Pierce TP, Palmieri M, et al: mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J Clin Invest. 123:767–781. 2013.PubMed/NCBI
18	Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
19	Grivennikov S, Karin E, Terzic J, et al: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 15:103–113. 2009. View Article : Google Scholar : PubMed/NCBI
20	Chumanevich AA, Poudyal D, Cui X, et al: Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis. 31:1787–1793. 2010. View Article : Google Scholar : PubMed/NCBI
21	Namba R, Young LJ, Abbey CK, et al: Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ. Clin Cancer Res. 12:2613–2621. 2006. View Article : Google Scholar : PubMed/NCBI
22	Yu H, Kortylewski M and Pardoll D: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 7:41–51. 2007. View Article : Google Scholar : PubMed/NCBI
23	Park E, Park J, Han SW, et al: NVP-BKM120, a novel PI3K inhibitor, shows synergism with a STAT3 inhibitor in human gastric cancer cells harboring KRAS mutations. Int J Oncol. 40:1259–1266. 2012.PubMed/NCBI
24	Farraye FA, Odze RD, Eaden J and Itzkowitz SH: AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 138:746–774.e4. 2010. View Article : Google Scholar : PubMed/NCBI
25	Gupta RB, Harpaz N, Itzkowitz S, et al: Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 133:1099–1105. 2007. View Article : Google Scholar : PubMed/NCBI
26	Sobala A, Herbst F, Novacek G and Vogelsang H: Colorectal carcinoma and preceding fistula in Crohn’s disease. J Crohns Colitis. 4:189–193. 2010.
27	Laukoetter MG, Mennigen R, Hannig CM, et al: Intestinal cancer risk in Crohn’s disease: a meta-analysis. J Gastrointest Surg. 15:576–583. 2011.
28	van Staa TP, Card T, Logan RF and Leufkens HG: 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut. 54:1573–1578. 2005.PubMed/NCBI
29	Rubin DT, LoSavio A, Yadron N, Huo D and Hanauer SB: Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol. 4:1346–1350. 2006. View Article : Google Scholar : PubMed/NCBI
30	Slomovitz BM and Coleman RL: The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res. 18:5856–5864. 2012. View Article : Google Scholar : PubMed/NCBI
31	Lauring J, Park BH and Wolff AC: The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Cancer Netw. 11:670–678. 2013.PubMed/NCBI
32	Lee YK, Park SY, Kim YM, et al: Suppression of mTOR via Akt-dependent and -independent mechanisms in selenium-treated colon cancer cells: involvement of AMPKα1. Carcinogenesis. 31:1092–1099. 2010.PubMed/NCBI
33	Zhang DM, Liu JS, Deng LJ, et al: Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis. 34:1331–1342. 2013. View Article : Google Scholar
34	Smrz D, Kim MS, Zhang S, et al: mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood. 118:6803–6813. 2011. View Article : Google Scholar : PubMed/NCBI
35	Fox R, Nhan TQ, Law GL, Morris DR, Liles WC and Schwartz SM: PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages. EMBO J. 26:505–515. 2007. View Article : Google Scholar : PubMed/NCBI
36	Kawauchi K, Ihjima K and Yamada O: IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3′-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol. 174:5261–5269. 2005.PubMed/NCBI
37	Donahue AC and Fruman DA: Proliferation and survival of activated B cells requires sustained antigen receptor engagement and phosphoinositide 3-kinase activation. J Immunol. 170:5851–5860. 2003. View Article : Google Scholar : PubMed/NCBI
38	Powell JD and Delgoffe GM: The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 33:301–311. 2010. View Article : Google Scholar : PubMed/NCBI
39	Memmott RM and Dennis PA: The role of the Akt/mTOR pathway in tobacco carcinogen-induced lung tumorigenesis. Clin Cancer Res. 16:4–10. 2010. View Article : Google Scholar : PubMed/NCBI
40	Ma J, Meng Y, Kwiatkowski DJ, et al: Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 120:103–114. 2010. View Article : Google Scholar : PubMed/NCBI
41	Farkas S, Hornung M, Sattler C, et al: Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis. Int J Colorectal Dis. 21:747–753. 2006.PubMed/NCBI
42	Deng L, Zhou JF, Sellers RS, et al: A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. Am J Pathol. 176:952–967. 2010. View Article : Google Scholar
43	Wu Y and Zhou BP: TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion. Br J Cancer. 102:639–644. 2010.
44	Hodge DR, Hurt EM and Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer. 41:2502–2512. 2005. View Article : Google Scholar : PubMed/NCBI
45	Grivennikov S, Karin E, Terzic J, et al: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 15:103–113. 2009. View Article : Google Scholar : PubMed/NCBI
46	Lippitz BE: Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 14:e218–e228. 2013. View Article : Google Scholar : PubMed/NCBI