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SMAD7 is a novel independent predictor of survival in patients with cutaneous melanoma

Published:September 26, 2018DOI:https://doi.org/10.1016/j.trsl.2018.09.002
      Overexpression of SMAD7—a hallmark inhibitor of transforming growth factor β (TGFβ) signaling—has been documented and related with adverse prognosis in a number of epithelial malignancies, suggesting that it may be responsible for resistance to TGFβ-induced growth arrest of cancer cells. The involvement of SMAD7 in development and progression of malignant melanoma is unclear, and its expression has not been characterized so far at the protein level in clinical melanoma tissue samples. We evaluated SMAD7 expression in 205 skin melanoma primary tumors by immunohistochemistry and correlated the findings with clinicopathological profiles of patients. Melanocytic SMAD7 was evidenced in 204 cases, and the expression pattern was predominantly nuclear. High expression of SMAD7 was positively associated with several features of tumor aggressiveness, for example, presence of ulceration (P < 0.001), higher tumor thickness (P < 0.001), and mitotic rate (P < 0.001), but not presence of regional or distant metastases. Moreover, high SMAD7 expression independently predicted unfavorable outcome: melanoma-specific survival (hazard ratio = 3.16, P < 0.001) and recurrence-free survival (hazard ratio = 2.88, P < 0.001). Taken together, our results underline the importance of TGFβ signaling in cancer and define SMAD7 as a marker of aggressive tumor behavior and adverse clinical outcomes in melanoma patients.

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      References

        • Massague J.
        TGFbeta in cancer.
        Cell. 2008; 134: 215-230
        • Samanta D.
        • Datta P.K.
        Alterations in the Smad pathway in human cancers.
        Front Biosci. 2012; 17 (Landmark Ed): 1281-1293
        • Markowitz S.
        • Wang J.
        • Myeroff L.
        • et al.
        Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.
        Science. 1995; 268: 1336-1338
        • Chen T.
        • Triplett J.
        • Dehner B.
        • et al.
        Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas.
        Cancer Res. 2001; 61: 4679-4682
        • Lynch M.A.
        • Nakashima R.
        • Song H.
        • et al.
        Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma.
        Cancer Res. 1998; 58: 4227-4232
        • Sakaguchi J.
        • Kyo S.
        • Kanaya T.
        • et al.
        Aberrant expression and mutations of TGF-beta receptor type II gene in endometrial cancer.
        Gynecol Oncol. 2005; 98: 427-433
        • Hahn S.A.
        • Schutte M.
        • Hoque A.T.
        • et al.
        DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
        Science. 1996; 271: 350-353
        • Ebisawa T.
        • Fukuchi M.
        • Murakami G.
        • et al.
        Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.
        J Biol Chem. 2001; 276: 12477-12480
        • Kavsak P.
        • Rasmussen R.K.
        • Causing C.G.
        • et al.
        Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.
        Mol Cell. 2000; 6: 1365-1375
        • Shi W.
        • Sun C.
        • He B.
        • et al.
        GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor.
        J Cell Biol. 2004; 164: 291-300
        • Cerutti J.M.
        • Ebina K.N.
        • Matsuo S.E.
        • Martins L.
        • Maciel R.M.
        • Kimura E.T.
        Expression of Smad4 and Smad7 in human thyroid follicular carcinoma cell lines.
        J Endocrinol Investig. 2003; 26: 516-521
        • Leng A.
        • Liu T.
        • He Y.
        • Li Q.
        • Zhang G.
        Smad4/Smad7 balance: a role of tumorigenesis in gastric cancer.
        Exp Mol Pathol. 2009; 87: 48-53
        • Theohari I.
        • Giannopoulou I.
        • Magkou C.
        • Nomikos A.
        • Melissaris S.
        • Nakopoulou L.
        Differential effect of the expression of TGF-beta pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior.
        APMIS. 2012; 120: 92-100
        • Boulay J.L.
        • Mild G.
        • Lowy A.
        • et al.
        SMAD7 is a prognostic marker in patients with colorectal cancer.
        Int J Cancer. 2003; 104: 446-449
        • Kim Y.H.
        • Lee H.S.
        • Lee H.J.
        • et al.
        Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas.
        Ann Oncol. 2004; 15: 574-580
        • Dowdy S.C.
        • Mariani A.
        • Reinholz M.M.
        • et al.
        Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer.
        Gynecol Oncol. 2005; 96: 368-373
        • Wang P.
        • Fan J.
        • Chen Z.
        • et al.
        Low-level expression of Smad7 correlates with lymph node metastasis and poor prognosis in patients with pancreatic cancer.
        Ann Surg Oncol. 2009; 16: 826-835
        • Xia H.
        • Ooi L.L.
        • Hui K.M.
        MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer.
        Hepatology. 2013; 58: 629-641
        • Javelaud D.
        • Delmas V.
        • Moller M.
        • et al.
        Stable overexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo.
        Oncogene. 2005; 24: 7624-7629
        • Javelaud D.
        • Mohammad K.S.
        • McKenna C.R.
        • et al.
        Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis.
        Cancer Res. 2007; 67: 2317-2324
        • DiVito K.A.
        • Trabosh V.A.
        • Chen Y.S.
        • et al.
        Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
        Pigment Cell Melanoma Res. 2010; 23: 795-808
        • Remmele W.
        • Stegner H.E.
        Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue.
        Pathologe. 1987; 8: 138-140
        • Kuang C.
        • Xiao Y.
        • Liu X.
        • et al.
        In vivo disruption of TGF-beta signaling by Smad7 leads to premalignant ductal lesions in the pancreas.
        Proc Natl Acad Sci USA. 2006; 103: 1858-1863
        • Halder S.K.
        • Beauchamp R.D.
        • Datta P.K.
        Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis.
        Exp Cell Res. 2005; 307: 231-246
        • Kleeff J.
        • Ishiwata T.
        • Maruyama H.
        • et al.
        The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.
        Oncogene. 1999; 18: 5363-5372
        • Nakao A.
        • Afrakhte M.
        • Moren A.
        • et al.
        Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.
        Nature. 1997; 389: 631-635
        • Van Belle P.
        • Rodeck U.
        • Nuamah I.
        • Halpern A.C.
        • Elder D.E.
        Melanoma-associated expression of transforming growth factor-beta isoforms.
        Am J Pathol. 1996; 148: 1887-1894
        • Reed J.A.
        • McNutt N.S.
        • Prieto V.G.
        • Albino A.P.
        Expression of transforming growth factor-beta 2 in malignant melanoma correlates with the depth of tumor invasion. Implications for tumor progression.
        Am J Pathol. 1994; 145: 97-104
        • Vincent K.M.
        • Postovit L.M.
        Investigating the utility of human melanoma cell lines as tumour models.
        Oncotarget. 2017; 8: 10498-10509
        • Humbert L.
        • Lebrun J.J.
        TGF-beta inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system.
        Cell Signal. 2013; 25: 490-500
        • Wiguna A.P.
        • Walden P.
        Role of IL-10 and TGF-beta in melanoma.
        Exp Dermatol. 2015; 24: 209-214
        • Shaul Y.D.
        • Yuan B.
        • Thiru P.
        • et al.
        MERAV: a tool for comparing gene expression across human tissues and cell types.
        Nucleic Acids Res. 2016; 44: D560-D566
        • Yu Y.
        • Gu S.
        • Li W.
        • et al.
        Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-beta signaling.
        Proc Natl Acad Sci USA. 2017; 114: 10113-10118
        • Kortylewski M.
        • Jove R.
        • Yu H.
        Targeting STAT3 affects melanoma on multiple fronts.
        Cancer Metastasis Rev. 2005; 24: 315-327
        • Boyer Arnold N.
        • Korc M.
        Smad7 abrogates transforming growth factor-beta1-mediated growth inhibition in COLO-357 cells through functional inactivation of the retinoblastoma protein.
        J Biol Chem. 2005; 280: 21858-21866
        • Yan X.
        • Chen Y.G.
        Smad7: not only a regulator, but also a cross-talk mediator of TGF-beta signalling.
        Biochem J. 2011; 434: 1-10