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Open Full Page Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. MicroRNA-211 enhances the oncogenicity of carcinogen-induced oral carcinoma by repressing TCF12 and increasing antioxidant activity Yi-Fen Chen1, Cheng-Chieh Yang1-3, Shou-Yen Kao2,3, Chung-Ji Liu2,4, Shu-Chun Lin1-3＊, Kuo-Wei Chang1-3* 1Institute of Oral Biology and 2Department of Dentistry, National Yang-Ming University, Taipei, Taiwan. 3Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan 4Department of Dentistry, MacKay Memorial Hospital, Taipei, Taiwan *Corresponding authors: Shu-Chun Lin, PhD Kuo-Wei Chang, DDS, PhD Institute of Oral Biology Department of Dentistry School of Dentistry School of Dentistry National Yang-Ming University National Yang-Ming University No. 155, Li-Nong St., Section 2 No. 155, Li-Nong St., Section 2 Taipei, Taiwan 112 Taipei, Taiwan 112 Fax: +8862-28264053 Fax: +8862-28264053 E-mail: [email protected] E-mail: [email protected] Running title: miR-211-TCF12-FAM213A activation in OSCC Conflict of interest: The authors declare no conflict of interest. Grant support: Shu-Chun Lin received grant MOST102-2628-B-010-006-MY3 from Ministry of Science and Technology. Kuo-Wei Chang received grant V103C-070 from Taipei Veterans General Hospital and grant 104AC-P504 from Aim for the Top University Plan from Department of Education. Shou-Yen Kao, Kuo-Wei Chang, and Cheng-Chieh Yang received grant for Health and Welfare Surcharge of tobacco products number MOHW104-TD-B-111-02 from Ministry of Health and Welfare for Excellence for Cancer Research. Keywords: FAM213A, HNSCC, microRNA, miR-211, Oral Cancer, TCF12 The authors assure that we will pay the color charge fees for Figures 1 and 7. 1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract miR-211 expression in human oral squamous cell carcinoma (OSCC) has been implicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mice tagged with green fluorescence protein. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically down-regulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that FAM213A, a peroxiredoxin-like anti-oxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment down-regulated TCF12 and up-regulated FAM213A by modulating miR-211 both in vitro and in vivo. Overall, our findings develop a mouse model that recapitulates the molecular and histopathological alterations of human OSCC pathogenesis and highlight a new microRNA-mediated oncogenic mechanism. 2 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Exposure to carcinogenic substances or viruses are the major etiological factors of head and neck squamous cell carcinoma (HNSCC) including oral squamous cell carcinoma OSCC (1-3). Many factor such as arecoline, are oxidative inducers (3). The five-year survival of OSCC remained low and this malignancy tended to relapse after treatment (4). Therefore, it is important to specify the molecular dis-regulation in the regulatory axis contributive to OSCC pathogenesis to develop therapeutic modalities (5). MicroRNAs (miRNAs) are small, non-coding RNAs of 19-25 nucleotides, which regulate physiological process or pathogenesis by targeting the mRNA to cause transcriptional repression or mRNA degradation (6,7). A number of disruptions in miRNA-target gene regulatory axes in OSCC have been discovered (8-13). miR-211 promoted OSCC oncogenicity and it served as an indicator for poor OSCC survival (14). We also showed that miR-211 targets TGFßRII, which is able to up-regulate c-myc expression in HNSCC (15). miR-211 also functions as an oncogenic miRNA in colorectal cancer (CRC) by targeting CHD5 (16). In addition, miR-211 promotes cell growth by targeting the p53 induced loc285194 LncRNA in CRC (17). A recent study has also specified that miR-211 prevents the ER induction by transcriptional repression of CHOP to modulate the survival of cells (18). Despite that miR-211 is a tumor suppressor in melanoma and some other cancers (19-21), the 3 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. function of miR-211 as an oncogenic molecule has become more evident in a fraction of malignancies (15-18). Transcription factor 12 (TCF12) (22), belongs to class I helix-loop-helix (HLH) protein family known as E protein, which can bind to DNA E-box site (23,24). TCF12 was shown to regulate the differentiation of lymphocytes or the development of neural or mesenchymal tissues (25-28). Recurrent mutations in TCF12 gene or the translocation fusion of a fragment of TCF12 with other molecules contribute to craniosynostosis or mesenchymal malignancies (29,30). In CRC, TCF12 expression correlated with metastasis by repression of E-cadherin (22). TCF12 has been reported targeted by miR-154 and miR-211 in melanoma cells and other types of normal cells (20,31,32). Nevertheless, the roles of TCF12 in OSCC and other cancers are still obscure. Reactive oxygen species (ROS) are intracellular chemical species that contain oxygen. Accumulated ROS causes oxidative stress and may induce cytotoxicity in cells (33), antioxidants are considered to be suppressors against cancers, as cancer cells seem to possess a higher tolerance of ROS than normal cells. However, recent evidence showed that the up-regulation of antioxidant protein Nrf2 might promote survival and resistance to therapies in cancer cells (34). A subpopulation of HNSCC cells carrying low ROS may exhibit more stemness and chemoresistance properties 4 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. (35). Peroxiredoxin (PRX) and thioredoxin (TRX) are two related families of antioxidant proteins. PRXs uptake H2O2 to become oxidized form. The oxidized PRXs then reduced by TRXs (36,37). Family with sequence similarity 213, member A (FAM213A) was discovered as one of the members in the PRX-like subfamily. Moreover, it also possesses an essential domain for TRXs activation (36). FAM213A was originally identified during fetal liver development and was activated in M-CSF stimulated monocytes (38). It was later found to protect cells from oxidative stress and modulates osteoclast differentiation (39). A recent study indicated that FAM213A could be one of the candidate antioxidants beneficial for high-altitude adaptation in Andean people (40). 4-nitroquinoline 1-oxide (4NQO) is a water-soluble carcinogen, which breaks DNA and induces ROS (41,42). The murine 4NQO tongue carcinogenesis has become a powerful model to address oral carcinogenesis (13,15). To address the oncogenic roles of miR-211 in the animal model, we generated miR-211 Tg mouse lines driven by the K14 promoter, which were tagged with enhanced green fluorescence protein (EGFP). We identified the enhancement of OSCC progression by 4NQO induction in this mouse model. Furthermore, we identified transcription factor TCF12 as a new target of miR-211 in OSCC cells. The enhanced FAM213A expression mediated by 5 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 24, 2016; DOI: 10.1158/0008-5472.CAN-15-1664 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. the repression of TCF12 through miR-211 expression reinforces OSCC oncogenesis and protects cells from the oxidative damages. Materials and Methods Cells OSCC cell lines SAS, OECM1, HSC3, FaDu, OC4, and SCC25; 293T cells and phoenix package cells; and six primary OSCC cells isolated from different tumors were used. Cell lines were achieved from ATCC or JCRB cell banks or derived according to previous protocols during 2012 - 2014 (11,13,15). All cell lines were authenticated by short tandem repeat analysis. The cultivation condition are described in Supplementary Table S1. SAS-miR-211, OECM1-miR-211, and control cell expressing GFP were established previously (14). The treatment conditions of miR-211 mimic/inhibitor/control (Applied Biosystems, Foster City, CA) were 60 or 30 nM for 48 or 72 h treatment. The dose of siTCF12 (Dharmacon, Lafayette, CO) and siFAM213A (Santa Cruz Biotech, Santa Cruz, CA) oligonucleotides were 60 nM for 30 or 48 h (Supplementary Table S2).
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