miR-1254 induced by NESG1 inactivates HDGF/DDX5-stimulated nuclear translocation of β-catenin and suppresses NPC metastasis

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/β-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells in vivo and in vitro. Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/β-catenin pathway and its downstream EMT signals. Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/β-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells in vivo and in vitro. Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/β-catenin pathway and its downstream EMT signals. IntroductionNasopharyngeal carcinoma (NPC) is one of the most common head-and-neck epithelial malignancies in southern China, which is also known as the Cantonese cancer.1Zhang L.F. Li Y.H. Xie S.H. Ling W. Chen S.H. Liu Q. Huang Q.H. Cao S.M. Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis.Chin. J. Cancer. 2015; 34: 350-357Crossref PubMed Scopus (111) Google Scholar The main etiologies of NPC are believed to be environmental factors, Epstein-Barr virus (EBV) exposure, and genetic factors.2Liu Y. Jiang Q. Liu X. Lin X. Tang Z. Liu C. Zhou J. Zhao M. Li X. Cheng Z. et al.Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway.EBioMedicine. 2019; 48: 386-404Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,3Chen Y.P. Chan A.T.C. Le Q.T. Blanchard P. Sun Y. Ma J. Nasopharyngeal carcinoma.Lancet. 2019; 394: 64-80Abstract Full Text Full Text PDF PubMed Scopus (937) Google ScholarPreviously, we identified a full-length NESG1 gene specifically expressed in human nasopharynx and trachea by screening different genes involving normal human nasopharyngeal and oral cavity mucosa of the soft palate.4Li Z. Yao K. Cao Y. Molecular cloning of a novel tissue-specific gene from human nasopharyngeal epithelium.Gene. 1999; 237: 235-240Crossref PubMed Scopus (18) Google Scholar A subsequent study showed that NESG1 might act as a tumor suppressor by inhibiting cell proliferation, migration, and invasion of NPC cells via modulating the cell cycle and the mitogen-activated protein kinase (MAPK) pathway.5Liu Z. Li X. He X. Jiang Q. Xie S. Yu X. Zhen Y. Xiao G. Yao K. Fang W. Decreased expression of updated NESG1 in nasopharyngeal carcinoma: its potential role and preliminarily functional mechanism.Int. J. Cancer. 2011; 128: 2562-2571Crossref PubMed Scopus (40) Google Scholar,6Liu Z. Luo W. Zhou Y. Zhen Y. Yang H. Yu X. Ye Y. Li X. Wang H. Jiang Q. et al.Potential tumor suppressor NESG1 as an unfavorable prognosis factor in nasopharyngeal carcinoma.PLoS ONE. 2011; 6: e27887Crossref PubMed Scopus (20) Google Scholar Also, we verified that reduced expression of NESG1 is an unfavorable factor modulating cell growth in non-small cell lung cancer (NSCLC).7Liu Z. Mai C. Yang H. Zhen Y. Yu X. Hua S. Wu Q. Jiang Q. Zhang Y. Song X. Fang W. Candidate tumour suppressor CCDC19 regulates miR-184 direct targeting of C-Myc thereby suppressing cell growth in non-small cell lung cancers.J. Cell. Mol. Med. 2014; 18: 1667-1679Crossref PubMed Scopus (45) Google Scholar Our recent study revealed that NESG1 interacted with VPS33B to regulate the Epidermal Growth Factor Receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/AKT/c-Myc/P53/miR-133a signal, which suppresses NPC growth.8Chen Y. Liu Z. Wang H. Tang Z. Liu Y. Liang Z. Deng X. Zhao M. Fu Q. Li L. et al.VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer.Int. J. Cancer. 2020; 146: 496-509Crossref PubMed Scopus (15) Google Scholar However, the detailed molecular basis for NESG1 to inhibit NPC metastasis is still unclear.MicroRNAs (miRNAs) are small non-coding RNAs with 21 to 23 nucleotides that inhibit their targeted genes.9Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (15577) Google Scholar An increasing number of studies have demonstrated that miRNAs may play a significant role in tumor pathogenesis.10Li Y. Liu X. Lin X. Zhao M. Xiao Y. Liu C. Liang Z. Lin Z. Yi R. Tang Z. et al.Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.Signal Transduct. Target. Ther. 2019; 4: 48Crossref PubMed Scopus (30) Google Scholar,11Deng X. Liu Z. Liu X. Fu Q. Deng T. Lu J. Liu Y. Liang Z. Jiang Q. Cheng C. Fang W. miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance.Mol. Ther. 2018; 26: 1066-1081Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar miR-486-3p acts as a tumor suppression factor in oral cancer.12Chou S.T. Peng H.Y. Mo K.C. Hsu Y.M. Wu G.H. Hsiao J.R. Lin S.F. Wang H.D. Shiah S.G. MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1.J. Exp. Clin. Cancer Res. 2019; 38: 281Crossref PubMed Scopus (47) Google Scholar Furthermore, many papers demonstrated that miRNAs could act as intermediate mediators participating in the modulation of some significant genes in tumor pathogenesis. For example, miR-139 inhibits hepatocellular carcinoma by directly targeting KPNA2.13Zan Y. Wang B. Liang L. Deng Y. Tian T. Dai Z. Dong L. MicroRNA-139 inhibits hepatocellular carcinoma cell growth through down-regulating karyopherin alpha Exp. Clin. Cancer Res. 2019; 38: PubMed Scopus Google Scholar in NPC and M. Luo R. Liu Y. L. Fu Z. Fu Q. Luo X. Chen Y. Deng X. Liang Z. et regulates nasopharyngeal carcinoma and through a positive with PubMed Scopus Google Scholar However, miRNAs in the pathogenesis of NPC induced by NESG1 to be we a reduced expression of miR-1254 in NPC, which is to NPC pathogenesis. Further, miR-1254, as a metastasis was induced by NESG1 and targeted HDGF to suppress and its downstream Our a NPC metastasis molecular which a for understanding the pathogenesis of suppresses NPC metastasis ability via inhibiting Wnt/β-catenin the functional of NESG1 in NPC, we expressed NESG1 in the NPC cells and The and protein were significantly in cells with cells via and with NESG1 the metastatic ability in NPC cells and by the and Boyden assays and Further, showed that expression of NESG1 suppressed the Wnt/β-catenin signaling pathway in and cells. The expression of and were was is induced by NESG1 through miRNAs in NPC, we used the assays cells miR-1254 was confirmed to be a positive downstream modulator of NESG1 via in NPC cells of miR-1254 by a in and cells to the EMT the and Boyden assays is induced by NESG1 through of expressed miRNAs and cells. and and Boyden assays for and cells with NESG1 NESG1 and miR-1254 and the binding and as the and assay of c-Myc binding to miR-1254 in and cells. and the of and in NESG1 cell by and was used as the explore the of NESG1 miR-1254 we used and to the to and to were identified the miR-1254 that reduced c-Myc expression miR-1254 expression in cell c-Myc acts as the downstream factor by Wnt/β-catenin we c-Myc as the factor of immunoprecipitation assay was used to the binding c-Myc and miR-1254 in and cells We performed an electrophoretic mobility shift assay to the of NPC cells to the and Also, the miR-1254 luciferase was A and were in cells demonstrated that the miR-1254 were Furthermore, assays showed that NESG1 the binding c-Myc and of miR-1254 of miR-1254 in assay was used to the expression of miR-1254 in NPC to nasopharynx we that miR-1254 expression was negatively correlated with clinical and metastasis The clinical of the NPC are in Further, that NPC with miR-1254 expression with expression A showed that the of miR-1254 expression was an independent prognostic factor for NPC Further, of miR-1254 and NESG1 were significantly in NPC to by NESG1 were positively correlated with miR-1254 expression of miR-1254 miR-1254 expression in NPC and expression of miR-1254 in NPC of miR-1254 in NPC and positive expression of miR-1254 in of of NPC Decreased expression of NESG1 and miR-1254 was in NPC to nasopharyngeal by to the and miR-1254 expression was positively correlated with expression of NESG1 in NPC suppresses NPC metastasis in vivo and in explore the role of miR-1254 in NPC, we and a of miR-1254 in and cell The was examined by with the of miR-1254 reduced cell migration and as by the and Boyden The of miR-1254 reversed the of the Further, we miR-1254 and its and cell and confirmed the in cells and We and cells the of In the of of and of of miR-1254 and metastasis In the metastasis in of in the and of in the miR-1254 and suppresses NPC metastasis in vivo and in miR-1254 expression was in and cells by to and Boyden assays for and cells with miR-1254 with confirmed the in and cells by the of and cells with used as an are for the of that metastasis directly and were used to the direct target of HDGF was to be a target Our study that HDGF could Wnt/β-catenin signaling in lung Q. Song X. Liu Z. Deng X. Luo R. C. Li R. Li Z. Zhao M. Chen Y. et and a by in Cancer Res. PubMed Scopus Google Scholar we that miR-1254 suppressed NPC metastasis by modulating of miR-1254 the expression of HDGF a miR-1254 reversed the we that of HDGF were in NPC to HDGF were negatively correlated with NESG1 as as miR-1254 in the NPC of of miR-1254 and HDGF the luciferase reporter with the and miR-1254 the and were HDGF reporter and the of miR-1254 and in the of binding miR-1254 and HDGF in cells was Further, the of HDGF in was also by miR-1254 HDGF miR-1254-overexpressing NPC cells cell metastasis the and Boyden assays HDGF restored the Factor in the miR-1254-overexpressing cells and reversed of and directly showed the binding of the of HDGF and of HDGF protein in NPC cells by expression of HDGF was in NPC to nasopharyngeal by to the miR-1254 expression was negatively correlated with expression of HDGF in NPC miR-1254 directly HDGF as confirmed by reporter and miR-1254 and HDGF were in HDGF were in miR-1254 complex miR-1254 was and Boyden assays of miR-1254-overexpressing cells with HDGF and HDGF were by blotting with with in and and HDGF the luciferase in miR-1254-overexpressing and cells. the of NESG1 by and showed an of with HDGF and of HDGF and was by the showed that the protein was in cells with the and with was the metastasis ability of the NESG1 miR-1254-overexpressing cells and In subsequent we that HDGF suppression in the and protein of A study that the complex could the of The of the of with is in Q. Song X. Liu Z. Deng X. Luo R. C. Li R. Li Z. Zhao M. Chen Y. et and a by in Cancer Res. PubMed Scopus Google Scholar with the HDGF reduced the with in NPC cells the suppression of the protein expression of and c-Myc also reduced HDGF Further, in cells of miR-1254 suppressed HDGF and Western showed that the expression of and were and was with the of miR-1254 NPC cells the of and and the of HDGF and in cells. of HDGF protein and and in and cells by and protein expression was reduced HDGF by and and HDGF reduced binding of with and c-Myc expression. HDGF expression and The luciferase was in miR-1254-overexpressing and cells. is a malignant carcinoma with and metastasis the sensitivity of NPC to and have significantly the metastasis a Y. S. K. H. M. T. K. T. of understanding for the role of Epstein-Barr virus and of nasopharyngeal PubMed Scopus Google Y.P. Wang Chen L. Liu X. Tang Y.P. Li Lin Sun Y. Ma J. A by and in with nasopharyngeal 2015; 26: Full Text Full Text PDF PubMed Scopus Google Scholar for the molecular of NPC metastasis the of NPC and the for tumor the tumor and metastatic of epithelial J. Mol. Google we and a gene Z. Yao K. Cao Y. Molecular cloning of a novel tissue-specific gene from human nasopharyngeal epithelium.Gene. 1999; 237: 235-240Crossref PubMed Scopus (18) Google Scholar in human nasopharyngeal that NESG1 as a tumor suppressor in NPC, and colorectal Z. Li X. He X. Jiang Q. Xie S. Yu X. Zhen Y. Xiao G. Yao K. Fang W. Decreased expression of updated NESG1 in nasopharyngeal carcinoma: its potential role and preliminarily functional mechanism.Int. J. Cancer. 2011; 128: 2562-2571Crossref PubMed Scopus (40) Google Z. Luo W. Zhou Y. Zhen Y. Yang H. Yu X. Ye Y. Li X. Wang H. Jiang Q. et al.Potential tumor suppressor NESG1 as an unfavorable prognosis factor in nasopharyngeal carcinoma.PLoS ONE. 2011; 6: e27887Crossref PubMed Scopus (20) Google Z. Mai C. Yang H. Zhen Y. Yu X. Hua S. Wu Q. Jiang Q. Zhang Y. Song X. Fang W. Candidate tumour suppressor CCDC19 regulates miR-184 direct targeting of C-Myc thereby suppressing cell growth in non-small cell lung cancers.J. Cell. Mol. Med. 2014; 18: 1667-1679Crossref PubMed Scopus (45) Google Y. Liu Z. Wang H. Tang Z. Liu Y. Liang Z. Deng X. Zhao M. Fu Q. Li L. et al.VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer.Int. J. Cancer. 2020; 146: 496-509Crossref PubMed Scopus (15) Google Scholar The precise mechanism for its role in NPC metastasis is known that of Wnt/β-catenin and its downstream EMT signaling in the of tumor X. Li Li Y.H. Luo Liu Liu C. Xie S. Liu Z. et and to inhibit tumor in hepatocellular Transduct. Target. Ther. 2020; PubMed Scopus Google X. S. Luo R. Li Y. Yu G. Y. Zhou Y. Liu Z. Liu Y. Y. et to and tumor in hepatocellular 2019; PubMed Scopus (40) Google Scholar In we that NESG1 suppressed migration and invasion by reducing the of and its downstream EMT as the c-Myc NESG1 as a tumor metastasis suppressor in explore the molecular basis of NESG1 in suppressing NPC migration and we used a to NESG1-modulated miRNAs in NPC cells and the cells. miR-1254 was induced by NESG1 in NPC. However, the molecular basis of miR-1254 is still have to the modulation of W. Zhou W. L. Wu X. Zhang P. Wang J. Liu G. Zhang W. Peng Y. Huang X. et regulates cell in human colorectal 2019; PubMed Scopus Google W. W. Huang Wang Y. The as a for non-small cell lung carcinoma Med. 2019; Scopus (15) Google X. Li X. Z. Y. Zhou B. proliferation, and migration of lung Cell. 2019; PubMed Scopus Google Scholar c-Myc as an factor that is in most human with Cancer. PubMed Scopus Google S. Y. an in and J. Med. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar and the expression of some miRNAs in Z. J. W. Wang R. J. Y. Yang H. Yang X. Fu Z. of the regulatory tumor metastasis and resistance in colorectal Med. PubMed Scopus Google Y. Li Z. Q. W. Sun J. Li J. Chen Li Z. Y. Zhou Y. et and by Res. 2019; PubMed Scopus (15) Google Scholar its as a also suppressed in as cell cycle and cell molecular Med. 2014; 4: PubMed Scopus (37) Google B. M. the of Cancer. PubMed Scopus Google Scholar we used to that were binding of c-Myc in the miR-1254 In with we confirmed that c-Myc modulated miR-1254 expression in c-Myc acts as a downstream factor by with Cancer. PubMed Scopus Google Scholar we NESG1 suppressed miR-1254 expression in miR-1254 to have a role in tumor as a tumor suppressor in and oral cell J. Liu X. Wang Wang Decreased expression of miR-1254 is with cancer and in Med. 2018; Google M. L. Yang C. Y. Lin L. H. He Y. Zhang Y. Yang L. miR-1254 inhibits cell proliferation, migration, and invasion by down-regulating in 2019; PubMed Scopus Google R. Zhang Y. Zhang X. as a in by Cancer Res. 2019; Scopus Google Scholar and in cancer and lung B. Chen P. Wang J. Wang L. M. Zhang R. He J. by directly targeting in human cancer.Int. J. 2018; Google H. Yang T. Sun Z. miR-1254 lung cancer cell by targeting PubMed Scopus Google Scholar In we the expression of miR-1254 in NPC. The showed that miR-1254 were significantly in NPC to miR-1254 expression was negatively correlated with clinical and metastasis positively correlated with and as an independent prognostic factor for NPC. we also that miR-1254 was positively correlated with NESG1 expression in NPC. miR-1254 was to be an unfavorable factor in NPC pathogenesis. that miR-1254 might as a tumor which was to the role of NESG1 in we the and molecular basis of miR-1254 in NPC. with we that miR-1254 suppressed NPC migration, and metastasis. In mechanism we with a luciferase reporter and assays and HDGF as the target of HDGF is a participating in of H. H. Liu W. Y. H. R. K. K. T. et of HDGF the Growth of In and In Res. 2015; Google Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google J. Ma H. Liu Z. H. L. cancer and cancer cells to Cancer Res. PubMed Scopus Google Scholar by its cancer cells to of by sensitivity to its in tumor J. Ma H. Liu Z. H. L. cancer and cancer cells to Cancer Res. PubMed Scopus Google Scholar In a we verified that expression of HDGF is a potential unfavorable prognostic factor for NPC S. Fang W. expression of growth factor with prognosis in human nasopharyngeal 2011; PubMed Scopus Google Scholar study that HDGF interacted with and induced of to and its downstream EMT and lung Q. Song X. Liu Z. Deng X. Luo R. C. Li R. Li Z. Zhao M. Chen Y. et and a by in Cancer Res. PubMed Scopus Google Scholar In subsequent we that HDGF reversed suppression by EMT demonstrated that to miR-1254 as a suppressor in miR-1254 NESG1 suppression in NPC, we used miR-1254 in NPC cells. The that NPC migration and invasion abilities were Molecular basis revealed that suppression of miR-1254 restored the of and its downstream EMT demonstrated that miR-1254 in suppression in NPC. A number of studies have that expression could Our may a a potential for NPC metastasis through miR-1254 and NPC cells and the Cancer of Sun were in with a of cells Cancer of was in with a of NPC and nasopharyngeal were by Fang NPC and were in Fang clinical for of the and the of the of Fang were assays were performed with the protein to the as Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google was performed as Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google Scholar were with in and with were in and with of miR-1254 was by and cell with and were designed by The was to the with miR-1254 and its and small RNAs for and c-Myc were from for and were from were to the was from NPC cell and normal by was performed as and genes were used as and gene for miR-1254, and are in was performed as The of are in The were with Molecular the to the of molecular with NPC cells were with the were with and and and The were with and by an was from and cells. The was as was the and luciferase reporter cells were respectively with and HDGF luciferase reporter are in with miR-1254 was were examined by the reporter as Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google was as The protein was with and with the the was and were by and invasion were to the with and the with the the was and as Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google were by the and of to were cells were the were by was by was performed as Z. S. Lu X. The expression and clinical of HDGF in Ther. 2015; Google Scholar The binding was in with the were a The are in was performed was used for are expressed as and independent were was used for and of was used for The was performed by were significant a IntroductionNasopharyngeal carcinoma (NPC) is one of the most common head-and-neck epithelial malignancies in southern China, which is also known as the Cantonese cancer.1Zhang L.F. Li Y.H. Xie S.H. Ling W. Chen S.H. Liu Q. Huang Q.H. Cao S.M. Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis.Chin. J. Cancer. 2015; 34: 350-357Crossref PubMed Scopus (111) Google Scholar The main etiologies of NPC are believed to be environmental factors, Epstein-Barr virus (EBV) exposure, and genetic factors.2Liu Y. Jiang Q. Liu X. Lin X. Tang Z. Liu C. Zhou J. Zhao M. Li X. Cheng Z. et al.Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway.EBioMedicine. 2019; 48: 386-404Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,3Chen Y.P. Chan A.T.C. Le Q.T. Blanchard P. Sun Y. Ma J. Nasopharyngeal carcinoma.Lancet. 2019; 394: 64-80Abstract Full Text Full Text PDF PubMed Scopus (937) Google ScholarPreviously, we identified a full-length NESG1 gene specifically expressed in human nasopharynx and trachea by screening different genes involving normal human nasopharyngeal and oral cavity mucosa of the soft palate.4Li Z. Yao K. Cao Y. Molecular cloning of a novel tissue-specific gene from human nasopharyngeal epithelium.Gene. 1999; 237: 235-240Crossref PubMed Scopus (18) Google Scholar A subsequent study showed that NESG1 might act as a tumor suppressor by inhibiting cell proliferation, migration, and invasion of NPC cells via modulating the cell cycle and the mitogen-activated protein kinase (MAPK) pathway.5Liu Z. Li X. He X. Jiang Q. Xie S. Yu X. Zhen Y. Xiao G. Yao K. Fang W. Decreased expression of updated NESG1 in nasopharyngeal carcinoma: its potential role and preliminarily functional mechanism.Int. J. Cancer. 2011; 128: 2562-2571Crossref PubMed Scopus (40) Google Scholar,6Liu Z. Luo W. Zhou Y. Zhen Y. Yang H. Yu X. Ye Y. Li X. Wang H. Jiang Q. et al.Potential tumor suppressor NESG1 as an unfavorable prognosis factor in nasopharyngeal carcinoma.PLoS ONE. 2011; 6: e27887Crossref PubMed Scopus (20) Google Scholar Also, we verified that reduced expression of NESG1 is an unfavorable factor modulating cell growth in non-small cell lung cancer (NSCLC).7Liu Z. Mai C. Yang H. Zhen Y. Yu X. Hua S. Wu Q. Jiang Q. Zhang Y. Song X. Fang W. Candidate tumour suppressor CCDC19 regulates miR-184 direct targeting of C-Myc thereby suppressing cell growth in non-small cell lung cancers.J. Cell. Mol. Med. 2014; 18: 1667-1679Crossref PubMed Scopus (45) Google Scholar Our recent study revealed that NESG1 interacted with VPS33B to regulate the Epidermal Growth Factor Receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/AKT/c-Myc/P53/miR-133a signal, which suppresses NPC growth.8Chen Y. Liu Z. Wang H. Tang Z. Liu Y. Liang Z. Deng X. Zhao M. Fu Q. Li L. et al.VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer.Int. J. Cancer. 2020; 146: 496-509Crossref PubMed Scopus (15) Google Scholar However, the detailed molecular basis for NESG1 to inhibit NPC metastasis is still unclear.MicroRNAs (miRNAs) are small non-coding RNAs with 21 to 23 nucleotides that inhibit their targeted genes.9Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (15577) Google Scholar An increasing number of studies have demonstrated that miRNAs may play a significant role in tumor pathogenesis.10Li Y. Liu X. Lin X. Zhao M. Xiao Y. Liu C. Liang Z. Lin Z. Yi R. Tang Z. et al.Chemical compound cinobufotalin potently induces FOXO1-stimulated cisplatin sensitivity by antagonizing its binding partner MYH9.Signal Transduct. Target. Ther. 2019; 4: 48Crossref PubMed Scopus (30) Google Scholar,11Deng X. Liu Z. Liu X. Fu Q. Deng T. Lu J. Liu Y. Liang Z. Jiang Q. Cheng C. Fang W. miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance.Mol. Ther. 2018; 26: 1066-1081Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar miR-486-3p acts as a tumor suppression factor in oral cancer.12Chou S.T. Peng H.Y. Mo K.C. Hsu Y.M. Wu G.H. Hsiao J.R. Lin S.F. Wang H.D. Shiah S.G. MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1.J. Exp. Clin. Cancer Res. 2019; 38: 281Crossref PubMed Scopus (47) Google Scholar Furthermore, many papers demonstrated that miRNAs could act as intermediate mediators participating in the modulation of some significant genes in tumor pathogenesis. For example, miR-139 inhibits hepatocellular carcinoma by directly targeting KPNA2.13Zan Y. Wang B. Liang L. Deng Y. Tian T. Dai Z. Dong L. MicroRNA-139 inhibits hepatocellular carcinoma cell growth through down-regulating karyopherin alpha Exp. Clin. Cancer Res. 2019; 38: PubMed Scopus Google Scholar in NPC and M. Luo R. Liu Y. L. Fu Z. Fu Q. Luo X. Chen Y. Deng X. Liang Z. et regulates nasopharyngeal carcinoma and through a positive with PubMed Scopus Google Scholar However, miRNAs in the pathogenesis of NPC induced by NESG1 to be we a reduced expression of miR-1254 in NPC, which is to NPC pathogenesis. Further, miR-1254, as a metastasis was induced by NESG1 and targeted HDGF to suppress and its downstream Our a NPC metastasis molecular which a for understanding the pathogenesis of NPC.

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