Primary microcephaly gene MCPH1 shows signatures of tumor suppressors and is regulated by miR-27a in oral squamous cell carcinoma

• Published in: PloS one Vol. 8; no. 3; p. e54643
• Main Authors: Venkatesh, Thejaswini, Nagashri, Mathighatta Nagaraj, Swamy, Shivananda S, Mohiyuddin, S M Azeem, Gopinath, Kodaganur S, Kumar, Arun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.03.2013; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; Agar; Animal tissues; Animals; Apoptosis; B cells; Biology; Brain; Breast cancer; Cancer therapies; Carcinoma, Squamous Cell - genetics; Cell Cycle Proteins; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell size; Chromosome 8; Cytoskeletal Proteins; Deoxyribonucleic acid; DNA; DNA methylation; DNA repair; Endometrial cancer; Endometrium; Ethics; Gene Expression Regulation, Neoplastic; Genes; Genes, Tumor Suppressor; HeLa Cells; Humans; Ionizing radiation; Loss of Heterozygosity; Low level; Medicine; Metastasis; Methylation; Mice; Mice, Inbred BALB C; Mice, Nude; Microcephaly; Microencephaly; MicroRNAs; MicroRNAs - genetics; Mouth Neoplasms - genetics; Mutation; Neoplasm Invasiveness; Neoplasm Transplantation; Nerve Tissue Proteins - genetics; Oncology; Oral cancer; Oral squamous cell carcinoma; Ovarian cancer; Prostate; Proteins; Squamous cell carcinoma; Suppressors; Surgery; Transcription; Ts gene; Tumor cell lines; Tumor suppressor genes; Tumors; India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054643

Mutations in the MCPH1 (microcephalin 1) gene, located at chromosome 8p23.1, result in two autosomal recessive disorders: primary microcephaly and premature chromosome condensation syndrome. MCPH1 has also been shown to be downregulated in breast, prostate and ovarian cancers, and mutated in 1/10 breast and 5/41 endometrial tumors, suggesting that it could also function as a tumor suppressor (TS) gene. To test the possibility of MCPH1 as a TS gene, we first performed LOH study in a panel of 81 matched normal oral tissues and oral squamous cell carcinoma (OSCC) samples, and observed that 14/71 (19.72%) informative samples showed LOH, a hallmark of TS genes. Three protein truncating mutations were identified in 1/15 OSCC samples and 2/5 cancer cell lines. MCPH1 was downregulated at both the transcript and protein levels in 21/41 (51.22%) and 19/25 (76%) OSCC samples respectively. A low level of MCPH1 promoter methylation was also observed in 4/40 (10%) tumor samples. We further observed that overexpression of MCPH1 decreased cellular proliferation, anchorage-independent growth in soft agar, cell invasion and tumor size in nude mice, indicating its tumor suppressive function. Using bioinformatic approaches and luciferase assay, we showed that the 3'-UTR of MCPH1 harbors two non-overlapping functional seed regions for miR-27a which negatively regulated its level. The expression level of miR-27a negatively correlated with the MCPH1 protein level in OSCC. Our study indicates for the first time that, in addition to its role in brain development, MCPH1 also functions as a tumor suppressor gene and is regulated by miR-27a.