ORIGINAL ARTICLE
Kindlin-3 and RASSF6 are probable biomarkers for predicting metastasis in cutaneous melanoma
 
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1
Department of Pathology, Gulhane Education and Research Hospital, Etlik, Ankara, Turkey
 
2
Department of Pathology, City Hospital, Bilkent, Ankara, Turkey
 
3
Department of Pathology, Abdurrahman Yurtaslan Oncology Education and Research Hospital, Ankara, Turkey
 
 
Submission date: 2020-09-13
 
 
Final revision date: 2020-12-01
 
 
Acceptance date: 2021-05-01
 
 
Publication date: 2022-01-19
 
 
Pol J Pathol 2021;72(3):237-244
 
KEYWORDS
TOPICS
ABSTRACT
It is well known that metastasis is the most crucial factor in determining the fate of the patient. The prognosis of melanoma is very poor at the stage of metastasis. Recently, several genes and proteins, including kindlin3, dioxin receptor (AhR), RASSF6, and claudin-11, which were shown as possible prognostic biomarkers for human tumours, were described. In this study, we focused on these proteins in melanoma within a clinical setting. Forty-three primary melanomas (PMs),
17 metastatic melanomas (MMs), 15 melanocytic nevi (MN), and two melanoma cell lines were included in this retrospective study. All proteins were investigated using immunohistochemistry, and analysis was performed using a semi-quantitative immunoreactive score (IRS). The nevus group showed lower RASSF6 and AhR IRS levels than PMs. RASSF6 and kindlin-3 levels in the PMs with metastasis (MwM) and also in PMs showing lymphovascular invasion were significantly lower. The logistic regression model also proved that kindlin-3 expression was a significant independent predictor of metastasis. The current study supports the role of kindlin-3 and RASSF6 as prognostic biomarkers in melanoma. Besides the prognostic roles of these proteins, they are probably potential candidates for target-oriented therapies for melanoma metastasis blocking.
REFERENCES (43)
1.
Azoury SC, Lange JR. Epidemiology, risk factors, prevention, and early detection of melanoma. Surg Clin North Am 2014; 94: 945-962.
 
2.
Hawryluk EB, Tsao H. Melanoma: clinical features and genomic insights. Cold Spring Harb Perspect Med 2014; 4: a015388.
 
3.
Ankeny JS, Labadie B, Luke J, et al. Review of diagnostic, prognostic, and predictive biomarkers in melanoma. Clin Exp Metastasis 2018; 35: 487-493.
 
4.
Mezzanotte JJ, Hill V, Schmidt ML, et al. RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells. Epigenetics 2014; 9: 1496-1503.
 
5.
Walesch SK, Richter AM, Helmbold P, Dammann RH. Claudin11 Promoter Hypermethylation Is Frequent in Malignant Melanoma of the Skin, but Uncommon in Nevus Cell Nevi. Cancers (Basel) 2015; 7: 1233-1243.
 
6.
Feng C, Wee WK, Chen H, et al. Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis. Cell Adh Migr 2017; 11: 419-433.
 
7.
Djaafri I, Khayati F, Menashi S, et al. A novel tumor suppressor function of Kindlin-3 in solid cancer. Oncotarget 2014; 5: 8970-8985.
 
8.
Contador-Troca M, Alvarez-Barrientos A, Barrasa E, et al. The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis. Carcinogenesis 2013; 34: 2683-2693.
 
9.
Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue – a review. Diagn Pathol 2014; 9: 221.
 
10.
Ercin ME, Bozdoğan Ö, Çavuşoğlu T, et al. Hypoxic Gene Signature of Primary and Metastatic Melanoma Cell Lines: Focusing on HIF-1beta and NDRG-1. Balkan Med J 2019; 37: 15-23.
 
11.
Abbas O, Miller DD, Bhawan J. Cutaneous malignant melanoma: update on diagnostic and prognostic biomarkers. Am J Dermatopathol 2014; 36: 363-379.
 
12.
Griewank KG. Biomarkers in melanoma. Scand J Clin Lab Invest Suppl 2016; 245: S104-112.
 
13.
Azorin P, Bonin F, Moukachar A, et al. Distinct expression profiles and functions of Kindlins in breast cancer. J Exp Clin Cancer Res 2018; 37: 281.
 
14.
Rognoni E, Ruppert R, Fässler R. The kindlin family: functions, signaling properties and implications for human disease. J Cell Sci 2016; 129: 17-27.
 
15.
Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta 2009; 1796: 114-128.
 
16.
Allen NP, Donninger H, Vos MD, et al. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene 2007; 26: 6203-6211.
 
17.
Iwasa H, Kudo T, Maimaiti S, et al. The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein. J Biol Chem 2013; 288: 30320-30329.
 
18.
Guo W, Dong Z, Guo Y, et al. Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma. Mol Carcinog 2016; 55: 1655-1666.
 
19.
Wen Y, Wang Q, Zhou C, et al. Decreased expression of RASSF6 is a novel independent prognostic marker of a worse outcome in gastric cancer patients after curative surgery. Ann Surg Oncol 2011; 18: 3858-3867.
 
20.
He Z, Zhao TT, Jin F, et al. Downregulation of RASSF6 promotes breast cancer growth and chemoresistance through regulation of Hippo signaling. Biochem Biophys Res Commun 2018; 503: 2340-2347.
 
21.
Zhou R, Qiu L, Liu X, et al. RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer. Oncotarget 2017; 8: 55162-55175.
 
22.
Ye HL, Li DD, Lin Q, et al. Low RASSF6 expression in pancreatic ductal adenocarcinoma is associated with poor survival. World Journal of Gastroenterology: WJG 2015; 21: 6621-6630.
 
23.
Yi M, Yang J, Chen X, et al. RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression. J Cell Physiol 2011; 226: 2360-2369.
 
24.
Helmbold P, Richter AM, Walesch S, et al. RASSF10 promoter hypermethylation is frequent in malignant melanoma of the skin but uncommon in nevus cell nevi. J Invest Dermatol 2012; 132: 687-694.
 
25.
Wang J, Hua W, Huang SK, et al. RASSF8 regulates progression of cutaneous melanoma through nuclear factor-κb. Oncotarget 2015; 6: 30165-30177.
 
26.
Baumholtz AI, Gupta IR, Ryan AK. Claudins in morphogenesis: Forming an epithelial tube. Tissue Barriers 2017; 5: e1361899-e1361899.
 
27.
Li J, Zhou C, Ni S, et al. Methylated claudin-11 associated with metastasis and poor survival of colorectal cancer. Oncotarget 2017; 8: 96249-96262.
 
28.
Shen Z, Cao B, Lin L, et al. The Clinical Signification of Claudin-11 Promoter Hypermethylation for Laryngeal Squamous Cell Carcinoma. Med Sci Monit 2017; 23: 3635-3640.
 
29.
Yang P, Zhang M, Liu X, Pu H. MicroRNA-421 promotes the proliferation and metastasis of gastric cancer cells by targeting claudin-11. Exp Ther Med 2017; 14: 2625-2632.
 
30.
Yang J, Liu X, Yuan X, Wang Z. miR-99b promotes metastasis of hepatocellular carcinoma through inhibition of claudin 11 expression and may serve as a prognostic marker. Oncol Rep 2015; 34: 1415-1423.
 
31.
Coutinho-Camillo CM, Lourenço SV, da Fonseca FP, Soares FA. Claudin expression is dysregulated in prostate adenocarcinomas but does not correlate with main clinicopathological parameters. Pathology 2011; 43: 143-148.
 
32.
Awsare NS, Martin TA, Haynes MD, et al. Claudin-11 decreases the invasiveness of bladder cancer cells. Oncol Rep 2011; 25: 1503-1509.
 
33.
Nissinen L, Siljamäki E, Riihilä P, et al. Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ. Exp Dermatol 2017; 26: 771-777.
 
34.
Gao L, van den Hurk K, Moerkerk PTM, et al. Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy. J Invest Dermatol 2014; 134: 2957-2966.
 
35.
Caruso M, Fung KY, Moore J, et al. Claudin-1 Expression Is Elevated in Colorectal Cancer Precursor Lesions Harboring the BRAF V600E Mutation. Transl Oncol 2014; 7: 456-463.
 
36.
Barouki R, Coumoul X, Fernandez-Salguero PM. The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 2007; 581: 3608-3615.
 
37.
Yi T, Wang J, Zhu K, et al. Aryl Hydrocarbon Receptor: A New Player of Pathogenesis and Therapy in Cardiovascular Diseases. Biomed Res Int 2018; 2018: 6058784.
 
38.
Safe S, Lee SO, Jin UH. Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target. Toxicol Sci 2013; 135: 1-16.
 
39.
Hidaka T, Fujimura T, Aiba S. Aryl Hydrocarbon Receptor Modulates Carcinogenesis and Maintenance of Skin Cancers. Front Med (Lausanne) 2019; 6: 194.
 
40.
Luecke S, Backlund M, Jux B, et al. The aryl hydrocarbon receptor (AHR), a novel regulator of human melanogenesis. Pigment Cell Melanoma Res 2010; 23: 828-833.
 
41.
Contador-Troca M, Alvarez-Barrientos A, Merino JM, et al. Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis. Mol Cancer 2015; 14: 148.
 
42.
Corre S, Tardif N, Mouchet N, et al. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat Commun 2018; 9: 4775.
 
43.
Mengoni M, Braun AD, Gaffal E, Tuting T. The aryl hydrocarbon receptor promotes inflammation-induced dedifferentiation and systemic metastatic spread of melanoma cells. Int J Cancer 2020; 147: 2902-2913.
 
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