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Prognostic Significance of TWEAK Expression in Colorectal Cancer and Effect of Its Inhibition on Invasion

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression.

Methods

To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays.

Results

CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK-mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples.

Conclusions

Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  2. Lin BR, Chang CC, Che TF, Chen ST, Chen RJ, Yang CY, et al. Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology. 2005;128:9–23.

    Article  PubMed  CAS  Google Scholar 

  3. Manfredi S, Bouvier AM, Lepage C, Hatem C, Dancourt V, Faivre J. Incidence and patterns of recurrence after resection for cure of colonic cancer in a well defined population. Br J Surg. 2006;93:1115–22.

    Article  PubMed  CAS  Google Scholar 

  4. Burkly LC, Michaelson JS, Hahm K, Jakubowski A, Zheng TS. TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine. 2007;40:1–16.

    Article  PubMed  CAS  Google Scholar 

  5. Winkles JA. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov. 2008;7:411–25.

    Article  PubMed  CAS  Google Scholar 

  6. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, et al. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem. 1997;272:32401–10.

    Article  PubMed  CAS  Google Scholar 

  7. Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, et al. TWEAK induces liver progenitor cell proliferation. J Clin Invest. 2005;115:2330–40.

    Article  PubMed  CAS  Google Scholar 

  8. Dogra C, Changotra H, Mohan S, Kumar A. Tumor necrosis factor-like weak inducer of apoptosis inhibits skeletal myogenesis through sustained activation of nuclear factor-kappaB and degradation of MyoD protein. J Biol Chem. 2006;281:10327–36.

    Article  PubMed  CAS  Google Scholar 

  9. Tiller G, Fischer-Posovszky P, Laumen H, Finck A, Skurk T, Keuper M, et al. Effects of TWEAK (TNF superfamily member 12) on differentiation, metabolism, and secretory function of human primary preadipocytes and adipocytes. Endocrinology. 2009;150:5373–83.

    Article  PubMed  CAS  Google Scholar 

  10. Perper SJ, Browning B, Burkly LC, Weng S, Gao C, Giza K, et al. TWEAK is a novel arthritogenic mediator. J Immunol. 2006;177:2610–20.

    PubMed  CAS  Google Scholar 

  11. Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, et al. The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration. J Biol Chem. 1999;274:33166–76.

    Article  PubMed  CAS  Google Scholar 

  12. Michaelson JS, Burkly LC. Therapeutic targeting of TWEAK/Fnl4 in cancer: exploiting the intrinsic tumor cell killing capacity of the pathway. Results Probl Cell Differ. 2009;49:145–60.

    Article  PubMed  CAS  Google Scholar 

  13. Winkles JA, Tran NL, Brown SA, Stains N, Cunliffe HE, Berens ME. Role of TWEAK and Fn14 in tumor biology. Front Biosci. 2007;12:2761–71.

    Article  PubMed  CAS  Google Scholar 

  14. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.

    Article  PubMed  CAS  Google Scholar 

  15. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12:895–904.

    Article  PubMed  CAS  Google Scholar 

  16. Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature. 1999;401:173–7.

    Article  PubMed  CAS  Google Scholar 

  17. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420–5.

    Article  PubMed  Google Scholar 

  18. Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A. Identification of a ligand for the death-domain-containing receptor Apo3. Curr Biol. 1998;8:525–8.

    Article  PubMed  CAS  Google Scholar 

  19. Baxter FO, Came PJ, Abell K, Kedjouar B, Huth M, Rajewsky K, et al. IKKβ/2 induces TWEAK and apoptosis in mammary epithelial cells. Development. 2006;133;3385–94.

    Article  Google Scholar 

  20. De A, Park JI, Kawamura K, Chen R, Klein C, Rauch R, et al. Intraovarian tumor necrosis factor-related weak inducer of apoptosis/ fibroblast growth factor-inducible-14 ligand-receptor system limits ovarian preovulatory follicles from excessive luteinization. Mol Endocrinol. 2006;20:2528–38.

    Article  PubMed  CAS  Google Scholar 

  21. Chacon MR, Richart C, Gómez JM, Megía A, Vilarrasa N, Fernández-Real JM, et al. Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity. Cytokine. 2006;33:129–37.

    Article  PubMed  CAS  Google Scholar 

  22. Ho DH, Vu H, Brown SA, Donohue PJ, Hanscom HN, Winkles JA. Soluble tumor necrosis factor-like weak inducer of apoptosis overexpression in HEK293 cells promotes tumor growth and angiogenesis in athymic nude mice. Cancer Res. 2004;64:8968–72.

    Article  PubMed  CAS  Google Scholar 

  23. Zhao H, Langerod A, Ji Y, Nowels KW, Nesland JM, Tibshirani R, et al. Different gene expression patterns in invasive lobular and ductal carcinomas of the breast. Mol Biol Cell. 2004;15:2523–36.

    Article  PubMed  CAS  Google Scholar 

  24. Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, et al. Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis. Biochem Biophys Res Commun. 2004;318:726–33.

    Article  PubMed  CAS  Google Scholar 

  25. Tran NL, McDonough WS, Donohue PJ, Winkles JA, Berens TJ, Ross KR, et al. The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors. Am. J. Pathol. 2003:162:1313–21.

    Article  PubMed  CAS  Google Scholar 

  26. Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, et al. Functional expression of TWEAK in human colonic adenocarcinoma cells. Int J Oncol. 2005;26:87–93.

    PubMed  CAS  Google Scholar 

  27. Wang D, Fung JN, Tuo Y, Hu L, Chen C. TWEAK/Fn14 promotes apoptosis of human endometrial cancer cells via caspase pathway. Cancer Lett. 2010:294:91–100.

    Article  PubMed  CAS  Google Scholar 

  28. Dionne S, Levy E, Levesque D, Seidman EG. PPARgamma ligand 15-deoxy-delta 12,4-prostaglandin J2 sensitizes human colon carcinoma cells to TWEAK-induced apoptosis. Anticancer Res. 2010;30:157–66.

    PubMed  CAS  Google Scholar 

  29. Nakayama M, Ishidoh K, Kojima Y, Harada N, Kominami E, Okumura K, et al. Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death. J Immunol. 2003;170:341–8.

    Google Scholar 

  30. Tran NL, McDonough WS, Savitch BA, Fortin SP, Winkles JA, Symons M, et al. Increased fibroblast growth factor-inducible 14ex pression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and correlate with poor patient outcome. Cancer Res. 2006;66:9535–42.

    Article  PubMed  CAS  Google Scholar 

  31. Fortin SP, Ennis MJ, Savitch BA, Carpentieri D, McDonough WS, Winkles JA, et al. Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function. Mol Cancer Res. 2009;7:1871–81.

    Article  PubMed  CAS  Google Scholar 

  32. Dai L, Gu L, Ding C, Qiu L, Di W. TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. Cancer Lett. 2009;283:159–67.

    Article  PubMed  CAS  Google Scholar 

  33. Lynch CN, Wang YC, Lund JK, Chen YW, Leal JA, Wiley SR. TWEAK induces angiogenesis and proliferation of endothelial cells. J Biol Chem. 1999;274:8455–9.

    Article  PubMed  CAS  Google Scholar 

  34. Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, et al. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity. 2001;15:837–46.

    Article  PubMed  CAS  Google Scholar 

  35. Yeung KC, Rose DW, Dhillon AS, Yaros D, Gustafsson M, Chatterjee D, et al. Raf kinase inhibitor protein interacts with NF-kappaBinducing kinase and TAK1 and inhibits NF-kappaB activation. Mol Cell Biol. 2001;21:7207–17.

    Article  PubMed  CAS  Google Scholar 

  36. Chatterjee D, Bai Y, Wang Z, Beach S, Mott S, Roy R, et al. RKIP sensitizes prostate and breast cancer cells to drug induced apoptosis. J Biol Chem. 2004;279:17515–23.

    Article  PubMed  CAS  Google Scholar 

  37. Fu Z, Smith PC, Zhang L, Rubin MA, Dunn RL, Yao Z, et al. Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst. 2003;95:878–89.

    Article  PubMed  CAS  Google Scholar 

  38. Schuierer MM, Bataille F, Hagan S, Kolch W, Bosserhoff AK. Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal regulated kinase signaling in melanoma cell lines. Cancer Res. 2004;64:5186–92.

    Article  PubMed  CAS  Google Scholar 

  39. Al-Mulla F, Hagan S, Behbehani AI, Bitar MS, George SS, Going JJ, et al. Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. J Clin Oncol. 2006;24:5672–9.

    Article  PubMed  CAS  Google Scholar 

  40. Prenen H, Tejpar S, Van Cutsem E. New strategies for treatment of KRAS mutant metastatic colorectal cancer. Clin Cancer Res. 2010;16:2921–6.

    Article  PubMed  CAS  Google Scholar 

  41. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by grants from National Science Council, Taiwan (NSC 97-2314-B-002-031-MY2). We thank Dr. Tung-Tien Sun (Department of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD) for providing the soluble form of TWEAK plasmid.

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Authors and Affiliations

  1. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Been-Ren Lin PhD, MD, Jin-Tung Liang PhD, MD, Po-Huang Lee PhD, MD & King-Jen Chang PhD, MD

  2. Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan

    Miao-Tzu Huang PhD & Szu-Ta Chen MD

  3. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

    Yung-Ming Jeng PhD, MD

  4. Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan

    Yue-Ju Li MS

  5. Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan

    King-Jen Chang PhD, MD & Cheng-Chi Chang PhD

  6. Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan

    Cheng-Chi Chang PhD

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  1. Been-Ren Lin PhD, MD
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Correspondence to Cheng-Chi Chang PhD.

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Lin, BR., Huang, MT., Chen, ST. et al. Prognostic Significance of TWEAK Expression in Colorectal Cancer and Effect of Its Inhibition on Invasion. Ann Surg Oncol 19 (Suppl 3), 385–394 (2012). https://doi.org/10.1245/s10434-011-1825-x

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  • DOI: https://doi.org/10.1245/s10434-011-1825-x

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