MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways Retraction in /10.3892/or.2023.8488

Kang,Kang; Zhang,Jing; Zhang,Xiaoyun; Chen,Zhao

doi:10.3892/or.2017.6074

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

Retraction in: /10.3892/or.2023.8488

Authors:
- Kang Kang
- Jing Zhang
- Xiaoyun Zhang
- Zhao Chen
View Affiliations

Affiliations: Department of Dermatology, Tangshan City Workers' Hospital, Tangshan, Hebei 063000, P.R. China
Published online on: November 2, 2017 https://doi.org/10.3892/or.2017.6074
Pages: 401-410

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Abstract

Melanoma is the seventh most common malignancy in females and the fifth most common cancer in males worldwide. An increasing number of studies have reported that microRNA (miRNA) dysregulation is frequently observed in various types of human cancers, including melanoma. Abnormally expressed miRNAs play an important role in melanoma formation and progression by serving as potential biomarkers and therapeutic targets. Recently, miRNA-326 (miR-326) has been reported to be differentially expressed in various types of tissues and play important roles in tumourigenesis and tumour development. However, the expression levels, biological roles and underlying mechanisms of miR-326 in melanoma remain unknown. In the present study, we demonstrated that miR-326 was significantly downregulated in melanoma tissues and cell lines. Functional assays revealed that the enforced expression of miR-326 suppressed melanoma cell proliferation and invasion and increased cell apoptosis in vitro. Using bioinformatic analysis, Kirsten rat sarcoma viral oncogene homolog (KRAS) was predicted as a potential target of miR-326. Luciferase reporter assay confirmed that miR-326 could directly target the 3'-untranslated region of KRAS. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-326 upregulation decreased the KRAS expression in melanoma cells at both the mRNA and protein level. Furthermore, KRAS was upregulated in melanoma tissues and inversely correlated with miR-326 expression. In addition, the KRAS knockdown phenocopied the tumour-suppressing effects of miR-326 overexpression on melanoma cells. The restoration of the expression of KRAS markedly reversed the antitumour effects induced by miR-326 overexpression in melanoma cells. Further experiments indicated that miR-326 inactivated the AKT and ERK signalling pathways in melanoma. Collectively, these results revealed that miR-326 serves as a tumour suppressor in melanoma by targeting KRAS and regulating the AKT and ERK signalling pathways, indicating that miR-326 may be a promising therapeutic target for melanoma patients.

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1	Trotter SC, Sroa N, Winkelmann RR, Olencki T and Bechtel M: A global review of melanoma follow-up guidelines. J Clin Aesthet Dermatol. 6:18–26. 2013.PubMed/NCBI
2	Linos E, Swetter SM, Cockburn MG, Colditz GA and Clarke CA: Increasing burden of melanoma in the United States. J Invest Dermatol. 129:1666–1674. 2009. View Article : Google Scholar : PubMed/NCBI
3	Terando A, Sabel MS and Sondak VK: Melanoma: Adjuvant therapy and other treatment options. Curr Treat Options Oncol. 4:187–199. 2003. View Article : Google Scholar : PubMed/NCBI
4	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
5	Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G and Testori A; EORTC Melanoma Group, : Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: Ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 55:111–121. 2016. View Article : Google Scholar : PubMed/NCBI
6	Eberle J, Kurbanov BM, Hossini AM, Trefzer U and Fecker LF: Overcoming apoptosis deficiency of melanoma-hope for new therapeutic approaches. Drug Resist Updat. 10:218–234. 2007. View Article : Google Scholar : PubMed/NCBI
7	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
8	Mimeault M and Batra SK: Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol. 3:32–42. 2012. View Article : Google Scholar : PubMed/NCBI
9	Lelli D, Pedone C and Sahebkar A: Curcumin and treatment of melanoma: The potential role of microRNAs. Biomed Pharmacother. 88:832–834. 2017. View Article : Google Scholar : PubMed/NCBI
10	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
11	Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI
12	Kozomara A and Griffiths-Jones S: miRBase: Integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39(Database): D152–D157. 2011. View Article : Google Scholar : PubMed/NCBI
13	Yu X, Li Z and Liu J: MiRNAs in primary cutaneous lymphomas. Cell Prolif. 48:271–277. 2015. View Article : Google Scholar : PubMed/NCBI
14	Bai J, Zhang Z, Li X and Liu H: MicroRNA-365 inhibits growth, invasion and metastasis of malignant melanoma by targeting NRP1 expression. Int J Clin Exp Pathol. 8:4913–4922. 2015.PubMed/NCBI
15	Ren JW, Li ZJ and Tu C: MiR-135 post-transcriptionally regulates FOXO1 expression and promotes cell proliferation in human malignant melanoma cells. Int J Clin Exp Pathol. 8:6356–6366. 2015.PubMed/NCBI
16	Sun M, Wang X, Tu C, Wang S, Qu J and Xiao S: microRNA-216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo. Cell Biol Int. Feb 22–2017.(Epub ahead of print). https://doi.org/10.1002/cbin.10754 View Article : Google Scholar
17	He L, Qu L, Wei L, Chen Y and Suo J: Reduction of miR 132 3p contributes to gastric cancer proliferation by targeting MUC13. Mol Med Rep. 15:3055–3061. 2017. View Article : Google Scholar : PubMed/NCBI
18	Yin Z, Xu M and Li P: miRNA-221 acts as an oncogenic role by directly targeting TIMP2 in non-small-cell lung carcinoma. Gene. 620:46–53. 2017. View Article : Google Scholar : PubMed/NCBI
19	Abdelmaksoud-Dammak R, Chamtouri N, Triki M, Saadallah-Kallel A, Ayadi W, Charfi S, Khabir A, Ayadi L, Sallemi-Boudawara T and Mokdad-Gargouri R: Overexpression of miR-10b in colorectal cancer patients: Correlation with TWIST-1 and E-cadherin expression. Tumour Biol. 39:10104283176959162017. View Article : Google Scholar : PubMed/NCBI
20	Zhu Y, Zhao H, Rao M and Xu S: MicroRNA-365 inhibits proliferation, migration and invasion of glioma by targeting PIK3R3. Oncol Rep. 37:2185–2192. 2017. View Article : Google Scholar : PubMed/NCBI
21	Shenouda SK and Alahari SK: MicroRNA function in cancer: Oncogene or a tumor suppressor? Cancer Metastasis Rev. 28:369–378. 2009. View Article : Google Scholar : PubMed/NCBI
22	Chen CZ: MicroRNAs as oncogenes and tumor suppressors. N Engl J Med. 353:1768–1771. 2005. View Article : Google Scholar : PubMed/NCBI
23	Wu L, Hui H, Wang LJ, Wang H, Liu QF and Han SX: MicroRNA-326 functions as a tumor suppressor in colorectal cancer by targeting the nin one binding protein. Oncol Rep. 33:2309–2318. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zhang ZL, Bai ZH, Wang XB, Bai L, Miao F and Pei HH: miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells. PLoS One. 10:e01188142015. View Article : Google Scholar : PubMed/NCBI
25	Sun C, Huang C, Li S, Yang C, Xi Y, Wang L, Zhang F, Fu Y and Li D: Hsa-miR-326 targets CCND1 and inhibits non-small cell lung cancer development. Oncotarget. 7:8341–8359. 2016. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Li M, Liu W, Zhu YF, Chen YL, Zhang BZ and Wang R: Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol. 45:1115–1119. 2006. View Article : Google Scholar : PubMed/NCBI
28	Chang Z, Ju H, Ling J, Zhuang Z, Li Z, Wang H, Fleming JB, Freeman JW, Yu D, Huang P, et al: Cooperativity of oncogenic K-ras and downregulated p16/INK4A in human pancreatic tumorigenesis. PLoS One. 9:e1014522014. View Article : Google Scholar : PubMed/NCBI
29	Przybojewska B, Jagiello A and Jalmuzna P: H-RAS, K-RAS, and N-RAS gene activation in human bladder cancers. Cancer Genet Cytogenet. 121:73–77. 2000. View Article : Google Scholar : PubMed/NCBI
30	Hubbard PA, Moody CL and Murali R: Allosteric modulation of Ras and the PI3K/AKT/mTOR pathway: Emerging therapeutic opportunities. Front Physiol. 5:4782014. View Article : Google Scholar : PubMed/NCBI
31	Calvo F, Agudo-Ibáñez L and Crespo P: The Ras-ERK pathway: Understanding site-specific signaling provides hope of new anti-tumor therapies. BioEssays. 32:412–421. 2010. View Article : Google Scholar : PubMed/NCBI
32	Latchana N, Ganju A, Howard JH and Carson WE III: MicroRNA dysregulation in melanoma. Surg Oncol. 25:184–189. 2016. View Article : Google Scholar : PubMed/NCBI
33	Cui L, Li Y, Lv X, Li J, Wang X, Lei Z and Li X: Expression of MicroRNA-301a and its functional roles in malignant melanoma. Cell Physiol Biochem. 40:230–244. 2016. View Article : Google Scholar : PubMed/NCBI
34	Wozniak M, Mielczarek A and Czyz M: miRNAs in melanoma: tumor suppressors and oncogenes with prognostic potential. Curr Med Chem. 23:3136–3153. 2016. View Article : Google Scholar : PubMed/NCBI
35	Varamo C, Occelli M, Vivenza D, Merlano M and Lo Nigro C: MicroRNAs role as potential biomarkers and key regulators in melanoma. Genes Chromosomes Cancer. 56:3–10. 2017. View Article : Google Scholar : PubMed/NCBI
36	Wu J, Li J, Ren J and Zhang D: MicroRNA-485-5p represses melanoma cell invasion and proliferation by suppressing Frizzled7. Biomed Pharmacother. 90:303–310. 2017. View Article : Google Scholar : PubMed/NCBI
37	Luan W, Qian Y, Ni X, Bu X, Xia Y, Wang J, Ruan H, Ma S and Xu B: miR-204-5p acts as a tumor suppressor by targeting matrix metalloproteinases-9 and B-cell lymphoma-2 in malignant melanoma. Onco Targets Ther. 10:1237–1246. 2017. View Article : Google Scholar : PubMed/NCBI
38	Cao L, Wang J and Wang PQ: MiR-326 is a diagnostic biomarker and regulates cell survival and apoptosis by targeting Bcl-2 in osteosarcoma. Biomed Pharmacother. 84:828–835. 2016. View Article : Google Scholar : PubMed/NCBI
39	Li Y, Gao Y, Xu Y, Ma H and Yang M: Down-regulation of miR-326 is associated with poor prognosis and promotes growth and metastasis by targeting FSCN1 in gastric cancer. Growth Factors. 33:267–274. 2015. View Article : Google Scholar : PubMed/NCBI
40	Wang S, Lu S, Geng S, Ma S, Liang Z and Jiao B: Expression and clinical significance of microRNA-326 in human glioma miR-326 expression in glioma. Med Oncol. 30:3732013. View Article : Google Scholar : PubMed/NCBI
41	Ji S, Zhang B, Kong Y, Ma F and Hua Y: miR-326 inhibits gastric cancer cell growth through down regulating NOB1. Oncol Res. 25:853–861. 2017. View Article : Google Scholar : PubMed/NCBI
42	Zhou J, Xu T, Yan Y, Qin R, Wang H, Zhang X, Huang Y, Wang Y, Lu Y, Fu D, et al: MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1). PLoS One. 8:e684692013. View Article : Google Scholar : PubMed/NCBI
43	Kefas B, Comeau L, Erdle N, Montgomery E, Amos S and Purow B: Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol. 12:1102–1112. 2010. View Article : Google Scholar : PubMed/NCBI
44	Wang R, Chen X, Xu T, Xia R, Han L, Chen W, De W and Shu Y: miR-326 regulates cell proliferation and migration in lung cancer by targeting phox2a and is regulated by HOTAIR. Am J Cancer Res. 6:173–186. 2016.PubMed/NCBI
45	Li J, Li S, Chen Z, Wang J, Chen Y, Xu Z, Jin M and Yu W: miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1. Tumour Biol. 37:13287–13294. 2016. View Article : Google Scholar : PubMed/NCBI
46	Cai M, Wang Z, Zhang J, Zhou H, Jin L, Bai R and Weng Y: Adam17, a target of mir-326, promotes EMT-induced cells invasion in lung adenocarcinoma. Cell Physiol Biochem. 36:1175–1185. 2015. View Article : Google Scholar : PubMed/NCBI
47	Du W, Liu X, Chen L, Dou Z, Lei X, Chang L, Cai J, Cui Y, Yang D, Sun Y, et al: Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness. Neuro Oncol. 17:243–253. 2015. View Article : Google Scholar : PubMed/NCBI
48	Janssen KP, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P, Rosty C, Abal M, El Marjou F, Smits R, et al: APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 131:1096–1109. 2006. View Article : Google Scholar : PubMed/NCBI
49	de Mello RA, Marques DS, Medeiros R and Araújo AM: Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol. 2:367–376. 2011. View Article : Google Scholar : PubMed/NCBI
50	Kim RK, Suh Y, Yoo KC, Cui YH, Kim H, Kim MJ, Gyu Kim I and Lee SJ: Activation of KRAS promotes the mesenchymal features of basal-type breast cancer. Exp Mol Med. 47:e1372015. View Article : Google Scholar : PubMed/NCBI
51	Ryu MJ, Liu Y, Zhong X, Du J, Peterson N, Kong G, Li H, Wang J, Salamat S, Chang Q, et al: Oncogenic Kras expression in postmitotic neurons leads to S100A8-S100A9 protein overexpression and gliosis. J Biol Chem. 287:22948–22958. 2012. View Article : Google Scholar : PubMed/NCBI
52	Deng M, Tang H, Zhou Y, Zhou M, Xiong W, Zheng Y, Ye Q, Zeng X, Liao Q, Guo X, et al: miR-216b suppresses tumor growth and invasion by targeting KRAS in nasopharyngeal carcinoma. J Cell Sci. 124:2997–3005. 2011. View Article : Google Scholar : PubMed/NCBI
53	Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992–3995. 2006. View Article : Google Scholar : PubMed/NCBI
54	Bhattacharya S, Socinski MA and Burns TF: KRAS mutant lung cancer: Progress thus far on an elusive therapeutic target. Clin Transl Med. 4:352015. View Article : Google Scholar : PubMed/NCBI
55	Schubbert S, Shannon K and Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 7:295–308. 2007. View Article : Google Scholar : PubMed/NCBI
56	Bodemann BO and White MA: Ral GTPases and cancer: Linchpin support of the tumorigenic platform. Nat Rev Cancer. 8:133–140. 2008. View Article : Google Scholar : PubMed/NCBI