Primary Microcephaly Gene MCPH1 Shows Signatures of Tumor Suppressors and Is Regulated by miR-27a in Oral Squamous Cell Carcinoma

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.

• Publication year

  2013

• Venue

  PLoS ONE

• Publication date

  2013-03-05

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0054643PMID 23472065PMCID 3589425
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Genetic heterogeneity in Pakistani microcephaly families

  2013cited by this paper
• Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin

  2012cited by this paper
• A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function.

  2012cited by this paper
• Identification and functional characterization of a primate‐specific E2F1 binding motif regulating MCPH1 expression

  2012cited by this paper
• Mutations in WDR62, encoding a centrosomal and nuclear protein, in Indian primary microcephaly families with cortical malformations

  2011cited by this paper
• CEP152 is a genome maintenance protein disrupted in Seckel syndrome

  2011cited by this paper
• MCPH1 regulates the neuroprogenitor division mode by coupling the centrosomal cycle with mitotic entry through the Chk1–Cdc25 pathway

  2011cited by this paper
• Microcephalin is a new novel prognostic indicator in breast cancer associated with BRCA1 inactivation

  2011cited by this paper
• Many roads lead to primary autosomal recessive microcephaly.

  2010cited by this paper
• ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target

  2010cited by this paper
• Craniosynostosis‐microcephaly with chromosomal breakage and other abnormalities is caused by a truncating MCPH1 mutation and is allelic to premature chromosomal condensation syndrome and primary autosomal recessive microcephaly type 1

  2010cited by this paper
• MCPH1/BRIT1 limits ionizing radiation-induced centrosome amplification

  2010cited by this paper
• Establishment of a Mouse Model with Misregulated Chromosome Condensation due to Defective Mcph1 Function

  2010cited by this paper
• BRIT1/MCPH1 Is Essential for Mitotic and Meiotic Recombination DNA Repair and Maintaining Genomic Stability in Mice

  2010cited by this paper
• A clinical and molecular genetic study of 112 Iranian families with primary microcephaly

  2010cited by this paper
• The Origins and Implications of Intratumor Heterogeneity

  2010cited by this paper
• Mechanisms of Inactivation of PTCH1 Gene in Nevoid Basal Cell Carcinoma Syndrome: Modification of the Two-Hit Hypothesis

  2010cited by this paper
• Comprehensive MicroRNA Profiling for Head and Neck Squamous Cell Carcinomas

  2010cited by this paper
• Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer.

  2010influential reference
• miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2.

  2010cited by this paper
• TNM Classification of Malignant Tumors, 7th edition

  2010cited by this paper
• Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly.

  2009cited by this paper
• Cell line cross-contamination: KB is not an oral squamous cell carcinoma cell line.

  2009cited by this paper
• Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1

  2009cited by this paper
• TNM Classification of Malignant Tumours, 7th Edition

  2009cited by this paper
• BRIT1/MCPH1 is a multifunctional DNA damage responsive protein mediating DNA repair-associated chromatin remodeling

  2009cited by this paper
• miR-Q: a novel quantitative RT-PCR approach for the expression profiling of small RNA molecules such as miRNAs in a complex sample

  2008cited by this paper
• MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis

  2008influential reference
• Microcephalin/MCPH1 Associates with the Condensin II Complex to Function in Homologous Recombination Repair*

  2008cited by this paper
• Use of the lambda Red recombinase system to rapidly generate mutants in Pseudomonas aeruginosa

  2008cited by this paper
• Differential regulation of centrosome integrity by DNA damage response proteins

  2008cited by this paper
• Evaluation of caspase-3 and caspase-8 deregulation in tongue squamous cell carcinoma, based on immunohistochemistry and computerised image analysis

  2008cited by this paper
• Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma

  2008cited by this paper
• Promoter characterization and regulation of expression of an imprinted gene SLC22A18AS.

  2008cited by this paper
• The influence of clinical and demographic risk factors on the establishment of head and neck squamous cell carcinoma cell lines.

  2007cited by this paper
• Frequent loss of heterozygosity in two distinct regions, 8p23.1 and 8p22, in hepatocellular carcinoma.

  2007cited by this paper
• Distance constraints between microRNA target sites dictate efficacy and cooperativity

  2007cited by this paper
• Cyclooxygenase-2 Is Involved in S100A2-Mediated Tumor Suppression in Squamous Cell Carcinoma

  2006cited by this paper
• BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.

  2006influential reference
• The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

  2005cited by this paper
• Choice of endogenous control for gene expression in nonsmall cell lung cancer

  2005cited by this paper
• Centrosome amplification, chromosome instability and cancer development.

  2005influential reference
• Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer

  2005cited by this paper
• Caspase‐3 expression is reduced, in the absence of cleavage, in terminally differentiated normal oral epithelium but is increased in oral squamous cell carcinomas and correlates with tumour stage

  2004cited by this paper
• Mutations in microcephalin cause aberrant regulation of chromosome condensation.

  2004cited by this paper
• The PAX5 oncogene is expressed in N-type neuroblastoma cells and increases tumorigenicity of a S-type cell line.

  2004cited by this paper
• Abnormal Methylation of Several Tumor Suppressor Genes in Sporadic Breast Cancer

  2003cited by this paper
• Gene Therapy for the Treatment of Oral Squamous Cell Carcinoma

  2003cited by this paper
• Multiple tumor suppressor pathways negatively regulate telomerase.

  2003cited by this paper
• Identification of microcephalin, a protein implicated in determining the size of the human brain.

  2002cited by this paper
• Two-stage polymerase chain reaction protocol allowing introduction of multiple mutations, deletions, and insertions, using QuikChange site-directed mutagenesis.

  2002cited by this paper
• CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future

  2002cited by this paper
• Glioblastoma Patients Epidermal Growth Factor Receptor , and Survival in Analysis of Complex Relationships between Age , p 53 , Updated

  2001cited by this paper
• Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

  2001cited by this paper
• Two-Stage PCR Protocol Allowing Introduction of Multiple Mutations , Deletions and Insertions Using QuikChange Site-Directed Mutagenesis

  1999cited by this paper
• Two-stage PCR protocol allowing introduction of multiple mutations, deletions and insertions using QuikChange Site-Directed Mutagenesis.

  1999cited by this paper
• Molecular characterization and delineation of subtle deletions in de novo “balanced” chromosomal rearrangements

  1998cited by this paper
• Deletion mapping defines three discrete areas of allelic imbalance on chromosome arm 8p in oral and oropharyngeal squamous cell carcinomas

  1997cited by this paper
• TNM classification of malignant tumors, fifth edition (1997)

  1997cited by this paper
• Loss of chromosome arm 8p loci in prostate cancer: Mapping by quantitative allelic imbalance

  1994cited by this paper

• Unveiling the Molecular Pathogenesis of MCPH: Insights From Drosophila Model System

  2025cites this paper
• Early Candida–Oral Tumor Interactions Suggest miRNA-Mediated Regulation of Inflammatory and Tumor-associated processes

  2025cites this paper
• Salivary Biomarkers for Oral Cancer Detection: Insights from Human DNA and RNA Analysis.

  2024cites this paper
• Microsatellite Instability and Loss of Heterozygosity as Prognostic Markers in Oral Squamous Cell Carcinoma: Molecular Mechanisms, Detection Techniques, and Therapeutic Strategies

  2024cites this paper
• Intronic miR-6741-3p targets the oncogene SRSF3: Implications for oral squamous cell carcinoma pathogenesis

  2024cites this paper
• The emerging role of MCPH1/BRIT1 in carcinogenesis

  2023cites this paper
• Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS): A Case Report and Review of the Literature

  2022cites this paper
• Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) using Next Generation Sequencing (NGS)

  2021cites this paper
• Salivary exosomal microRNAs as biomarkers for head and neck cancer detection—a literature review

  2021cites this paper
• The N-terminal BRCT domain determines MCPH1 function in brain development and fertility

  2021cites this paper
• Evaluating the role of microRNAs alterations in oral squamous cell carcinoma.

  2020cites this paper
• Analysis of the “centrosome-ome” identifies MCPH1 deletion as a cause of centrosome amplification in human cancer

  2020cites this paper
• microRNAs in oral cancer: Moving from bench to bed as next generation medicine.

  2020cites this paper
• MicroRNA Profiling in Non-Small Cell Lung Cancer and its Implications for the Disease Pathogenesis

  2020cites this paper
• Primary microcephaly with an unstable genome

  2020cites this paper
• Cancer‐associated mutations in the condensin II subunit CAPH2 cause genomic instability through telomere dysfunction and anaphase chromosome bridges

  2020cites this paper
• Investigation of promoter methylation of MCPH1 gene in circulating cell-free DNA of brain tumor patients

  2020cites this paper
• BRIT1 dysfunction confers synergistic inhibition of hepatocellular carcinoma by targeting poly (ADP-ribose) polymerases and PI3K.

  2020cites this paper
• MiR-27a: A Novel Biomarker and Potential Therapeutic Target in Tumors

  2019cites this paper
• A robust penalized Cox prediction model for detection of mis-spliced transcripts with prognostic impacts in adult de novo Acute Myeloid Leukemia

  2018cites this paper
• Overexpression of MCPH1 inhibits the migration and invasion of lung cancer cells

  2018cites this paper
• Comprehensive review on the molecular genetics of autosomal recessive primary microcephaly (MCPH).

  2018cites this paper
• Clinical Significance of microRNA Polymorphisms and Expression Profiles in Oral Cancer Development

  2018cites this paper
• PTPH1 immunohistochemical expression and promoter methylation in breast cancer patients from India: A retrospective study

  2018cites this paper
• Overexpression of McPh 1 inhibits the migration and invasion of lung cancer cells

  2018cites this paper
• Silencing BRIT1 Facilitates the Abilities of Invasiveness and Migration in Trophoblast Cells

  2018cites this paper
• Serum miRNA-27a and miRNA-18b as potential predictive biomarkers of hepatitis C virus-associated hepatocellular carcinoma

  2018cites this paper
• Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma

  2018cites this paper
• PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression

  2017cites this paper
• miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4

  2017cites this paper
• A Looking-Glass of Non-Coding RNAs in Oral Cancer

  2017cites this paper
• Comparison of the miRNA expression profiles in fresh frozen and formalin-fixed paraffin-embedded tonsillar tumors

  2017cites this paper
• Overexpression of MCPH1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G2/M phase in lung cancer cells.

  2016cites this paper
• The DNA damage response molecule MCPH1 in brain development and beyond.

  2016cites this paper
• Expression of Sp7 in Satb2-induced osteogenic differentiation of mouse bone marrow stromal cells is regulated by microRNA-27a

  2016cites this paper
• Overexpression of MCPH 1 inhibits uncontrolled cell growth by promoting cell apoptosis and arresting the cell cycle in S and G 2 / M phase in lung cancer cells

  2015cites this paper
• MicroRNAs as Important Players and Biomarkers in Oral Carcinogenesis

  2015cites this paper
• Convergent Science Physical Oncology

  2015cites this paper
• Molecular and Biological Aspects of Microcephalin Gene: Directions in Brain Tumor and Methylation

  2015cites this paper
• Tumor Suppressor MicroRNA-27a in Colorectal Carcinogenesis and Progression by Targeting SGPP1 and Smad2

  2014cites this paper
• Uncovering Differential Multi-microRNA Signatures of Acute Myeloid and Lymphoblastic Leukemias with a Machine-Learning-Based Network Approach

  2014cites this paper
• Key Role of Promoter Methylation and Inactivation of MCPH1 Gene in Brain Tumors

  2014cites this paper
• MicroRNA‐206 induces G1 arrest in melanoma by inhibition of CDK4 and Cyclin D

  2014cites this paper
• MicroRNAs and head and neck cancer: reviewing the first decade of research.

  2014cites this paper
• Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model

  2014cites this paper
• Uncovering low-dimensional, miR-based signatures of acute myeloid and lymphoblastic leukemias with a machine-learning-driven network approach.

  2014cites this paper
• MicroRNA-125a Reduces Proliferation and Invasion of Oral Squamous Cell Carcinoma Cells by Targeting Estrogen-related Receptor (cid:2)

  2014cites this paper
• Deregulation of Microcephalin and ASPM Expression Are Correlated with Epithelial Ovarian Cancer Progression

  2014cites this paper
• A Meta-Analysis of Multiple Matched Copy Number and Transcriptomics Data Sets for Inferring Gene Regulatory Relationships

  2014cites this paper
• Emerging roles of MCPH1: expedition from primary microcephaly to cancer.

  2014cites this paper
• MicroRNA-125a Reduces Proliferation and Invasion of Oral Squamous Cell Carcinoma Cells by Targeting Estrogen-related Receptor α

  2014cites this paper
• MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues.

  2013cites this paper