BALB/c nude mice 6 weeks old were inoculated with glioma C6 cell-line and the efficacy of the different amount of Etanidazole-discs and Taxol-microspheres was investigated. Poly (D,L-lactic-co-glycolic acid) (PLGA) was used as the main encapsulating polymer and polyethylene glycol was added to increase the porosity. The 1% drug loading microspheres of each drug were produced by spray drying and the discs were obtained by compressing the Etanidazole-microspheres. Intra-tumoral injection followed by irradiation resulted in high systemic dosage and thus systemic toxicity. Tumors grown for 6 days, 9 days and 16 days were implanted with 0.5 mg or 1.0 mg or 1.5 mg of the drug. A radiation dosage of 2 Gy each time for a number of times was given for animals implanted with Etanidazole and no irradiation was given for animals implanted with Taxol. Increasing the number of doses clearly decreased the rate of tumor growth. The increase in the amount of drug on smaller sized tumors controlled the tumor better and there was agglomeration of the microspheres resulting in deviation of release profile of the drug as compared to the in vitro studies. It was observed that 1.0 mg of Taxol given to a tumor grown for 6 days was able to suppress the tumor for a total period of approximately two months and no tumor resurrection was observed during the second month. / Singapore-MIT Alliance (SMA)

No description available.

No description available.

In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.

Receptor tyrosine kinases such as ErbB2 contribute greatly to human malignant transformation, but the role that other receptors such as ß2 adrenergic receptor (B2 AR)play in cancer is ill defined. Furthermore, while some GTPases such as Ras and RhoA promote oncogenesis, RhoB has been suggested to have tumor suppressive activity. In this thesis the tumor suppressive activity of ß2 adrenergic receptors through blockade of the Ras/Raf/Mek/Erk pathway is demonstrated. Furthermore, this thesis provides strong evidence in support of a tumor suppressive activity of RhoB, but not RhoA, in delaying EbB2 mammary oncogenesis in a transgenic mouse model. Chapter 1 describes a chemical biology approach that identifies a beta 2 adrenergic receptor agonist, ARA-211 (also known as pirbuterol) that suppresses the growth of cultured cells and of human tumors grown in nude mice by a mechanism involving stimulation of the ß2 AR, cAMP production and activation of PKA, which in turn leads to the inactivation of C-Raf, Mek1/2 and Erk1/2. Chapter 2 describes the translation of these findings by ex-vivo treatment of fresh human tumor biopsies, with the ultimate goal of validating this novel therapeutic approach. Chapter 3 describes the generation of transgenic mice that over express ErbB2 along with either RhoB or RhoA to determine the effects of these two small GTPases on ErbB2-mediated mammary tumorigenesis. The findings indicate that overexpression of RhoB, but not RhoA, results in decreased multiplicity and delay in the tumor onset mediated by ErbB2 overexpression. In summary, this thesis work resulted in the discovery of how crosstalk between the ß2 AR/cAMP/PKA circuit with the Raf/Mek/Erk1/2 cascade leads to tumor suppression; and the discovery of the suppression of ErbB2-mediated breast cancer by the GTPase RhoB.

During every cell cycle and upon exogenous stress, tumor suppression programs are engaged to ensure genomic stability. In response to replicative aging and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells. Several lines of evidence suggest that escape from senescence is a crucial early step in oncogenic progression. A major challenge in the cancer field is to combine genomic information regarding cancer-associated genetic changes with high-throughput functional studies, in order to confirm genetic requirements and pinpoint biological roles of these perturbed genes in oncogenesis. Furthermore, a complete genetic understanding of replicative senescence, and how it might be bypassed, is lacking. We describe here two genome scale loss-of-function genetic screens that interrogate these tumor suppressor programs. We utilized a unique sensitization approach to isolate senescence pathways and unmask compensatory mechanisms that may have been difficult to identify in previous studies. These genetic screens have generated comprehensive and validated datasets of putative senescence and p53 pathway genes. We present this dataset as a high-quality resource for further investigation into these biological pathways. We have uncovered several genes in distinct biological pathways which have not been demonstrated to have a functional role in senescence, and which may be putative tumor suppressors. We have identified BRD7 and BAF180, two SWI/SNF components, as critical regulators of p53. BRD7 and BAF180 are required for p53 activity and p21 expression during replicative and oncogene-induced senescence, and evidence suggests that they are inactivated in human cancer. In addition, we have uncovered a role for the deubiquitinating enzyme USP28 in the regulation of p53 accumulation during senescence, such that loss of USP28 results in bypass of the senescence program. We have also investigated several other novel senescence genes including SEMA6A, SEMA3b, and TMEM154. We have found that the expression of these genes is highly regulated during senescence by distinct means, including both p53-dependent and p53-independent mechanisms. These results demonstrate the efficacy of our sensitized screening approach, and also highlight the emerging view that the senescence program requires the combined action of multiple biological pathways for its execution.

La protéine p53 est surtout étudiée pour sa capacité à empêcher la prolifération de cellules dont le génome est endommagé. Toutefois, en analysant les souris p53Δ31/Δ31 qui expriment une protéine p53 hyperactive, notre laboratoire a découvert un rôle inattendu de p53 dans la régulation du métabolisme des télomères. Ces souris modélisent la dyskératose congénitale (DC), un syndrome d’insuffisance médullaire héréditaire (SIMH) causé par un dysfonctionnement télomérique. Mon projet de thèse a combiné les analyses de modèles murins et de lignées cellulaires humaines afin d’approfondir l'étude de cette nouvelle fonction de p53 et de mieux comprendre le rôle de la voie p53 dans le développement des SIMH.En poursuivant notre analyse du modèle murin p53Δ31, nous avons montré que les cellules p53Δ31/Δ31 présentent une diminution d’expression de 12 gènes mutés dans l’anémie de Fanconi (AF), un autre SIMH étroitement lié à la DC. De plus, ces cellules montrent une capacité réduite à réparer les ponts inter-brins de l’ADN, une caractéristique typique de l’AF. Notre étude suggère que l’activation soutenue de p53 pourrait ainsi contribuer aux similitudes cliniques entre ces deux syndromes. Par ailleurs, nous avons identifié par quel mécanisme p53 régule négativement le métabolisme des télomères et la voie Fanconi de réparation de l’ADN. Ce mécanisme de régulation indirect, via p21 et E2F4, est très conservé entre la souris et l’Homme. De fait, les cellules p53Δ31/Δ31 constituent un outil puissant pour identifier de nouvelles cibles de p53 réprimées par ce mécanisme. Ainsi, elles nous ont permis de montrer que deux gènes essentiels pour la structure des centromères sont réprimés par p53.L’activation de p53 est clairement impliquée dans les étapes ultimes d’une insuffisance médullaire, mais le rôle d’une suractivation de p53 dans l’initiation d’un SIMH chez l'Homme reste, à ce jour, controversé. En effet, une mutation inactivatrice de la ribonucléase PARN a été trouvée chez des patients atteints de DC. Il a été proposé que cette protéine déstabilise l’ARNm de p53 tout en favorisant la maturation de l’ARN de la télomérase, si bien que les conséquences d’une inactivation de PARN restent mal comprises. Au cours de ma thèse, j'ai également étudié de nouveaux modèles murins et établi des modèles cellulaires humains pour déterminer l’implication d’une activation de p53 dans l’initiation d’un SIMH chez l’homme. Les résultats en cours, particulièrement prometteurs, devraient notamment déterminer l’impact d’une déficience en Parn sur la voie de régulation de p53.En conclusion, nous avons montré qu’une activation soutenue de p53 conduit à des phénotypes principalement associés aux SIMH. Par ailleurs, nous avons montré que p53 réprime de nombreux gènes impliqués dans la maintenance du génome, ce qui peut sembler surprenant au regard du concept de « gardien du génome » communément attribué à p53, et nous a amené à rediscuter ce concept. Ainsi, les résultats obtenus pendant ma thèse devraient permettre de mieux comprendre les mécanismes impliqués dans l’insuffisance médullaire, la suppression tumorale et le vieillissement. / The p53 protein is mostly studied for its capacity to prevent the proliferation of cells with damaged genome. However, while studying p53Δ31/Δ31 mice that express a hyperactive p53 protein, our laboratory uncovered an unexpected role of p53 in the regulation of telomere metabolism. These mice model dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS) caused by defects in telomere maintenance. My PhD project combined analyses of mouse models and human cell lines to extend the study of this new function for p53 and to understand the role of the p53 pathway in the development of IBMFS.By extending our analysis of the p53Δ31 mouse model, we revealed that the p53Δ31/Δ31 cells exhibit decreased expression levels for 12 genes mutated in Fanconi anemia (FA), another IBMFS closely related to DC. Furthermore, these cells display a reduced capacity to repair DNA inter-strand crosslinks, a typical feature of FA cells. Our study suggests that a sustained activation of p53 might actually contribute to the clinical overlap between both syndromes. Importantly, we identified the mechanism used by p53 to downregulate telomere metabolism and the FA DNA repair pathway. This regulatory mechanism is indirect, via p21 and E2F4, and largely conserved between mice and humans. In fact, the p53Δ31/Δ31 cells constitute a powerful tool to find p53 target genes downregulated through this regulatory pathway. Accordingly, they were useful to show that two genes essential for centromere structure are also downregulated by p53.p53 activation is clearly involved in the final stages of bone marrow failure, but to-date, the role of p53 hyperactivation in the initiation of IBMFS remains controversial. Indeed, an inactivating mutation of the PARN gene, encoding a ribonuclease, was found in patients with DC. This protein was proposed to destabilize the p53 mRNA while promoting the maturation of the telomerase RNA, so that the consequences of PARN inactivation remain poorly understood. During my thesis, I also studied new mouse models and established human cellular models to determine the contribution of p53 activation in initiating IBMFS in humans. The current results, which are particularly promising, should notably determine the impact of Parn deficiency on the p53 regulatory pathway.In conclusion, we demonstrated that a sustained activation of p53 leads to phenotypes mainly associated with IBMFS. In addition, we showed that p53 suppresses many genes involved in genome maintenance, which may seem surprising in view of the concept of "guardian of the genome" commonly attributed to p53, leading us to revisit this concept. Hence, the results obtained during my thesis should help to better understand the mechanisms involved in bone marrow failure, tumor suppression and aging.

In the US, the incidence and mortality rates of hepatocellular carcinoma (HCC) are alarmingly increasing since no effective therapy is available for the advanced disease. Activation of IGF signaling is a major oncogenic event in diverse cancers, including HCC. Insulin-like growth factor binding protein-7 (IGFBP7) inhibits IGF signaling by binding to IGF-1 receptor (IGF-1R) and functions as a potential tumor suppressor for hepatocellular carcinoma (HCC). IGFBP7 abrogates tumors by inducing cancer-specific senescence and apoptosis and inhibiting angiogenesis. We now document that Igfbp7 knockout (Igfbp7-/- ) mouse shows constitutive activation of IGF signaling, presents with pro-inflammatory and immunosuppressive microenvironment, and develops spontaneous tumors in lungs and liver and markedly accelerated carcinogen-induced HCC. Loss of Igfbp7 resulted in increased proliferation and decreased senescence in hepatocytes and mouse embryonic fibroblasts that could be blocked by an IGF-1 receptor inhibitor. A significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- livers which was associated with marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immune competent mice, which could be abolished by depletion of CD4+ or CD8+ T lymphocytes. Our studies unravel modulation of immune response as a novel component of pleiotropic mechanisms by which IGFBP7 suppresses HCC. Even though HCC has an immunosuppressive milieu, immune targeted therapies are beginning to demonstrate significant objective responses in clinical trials. IGFBP7 might be an effective anti-HCC therapeutic by directly inhibiting cancer cells and stimulating an anti-tumor immune response.

Les kinases régulées par les signaux extracellulaires (ERK1/2) régulent une multitude de processus cellulaires, incluant la prolifération, la survie et la différenciation. Ces kinases représentent l’élément terminal de la voie ERK/MAPK, laquelle est activée dans près de 30% de tous les cancers humains et donc généralement perçue comme étant un effecteur critique de la progression tumorale. Cependant, une accumulation d’observations suggèrent que les kinases ERK pourraient également induire la suppression tumorale. Le but premier de cette thèse est de démontrer comment la signalisation par ERK peut contribuer à la suppression tumorale et de concilier les mécanismes impliqués avec son rôle dans la progression du cancer. Puisque nos travaux ont une incidence sur les bénéfices attendus de certaines thérapies actuellement en développement, le deuxième objectif de la thèse est de proposer de nouvelles stratégies thérapeutiques pour combattre le cancer. Nous avons démontré qu’une hyperactivation des kinases ERK induit la sénescence cellulaire. Le mécanisme implique la dégradation sélective et dépendante du protéasome de nombreuses protéines, ce que nous avons nommé le SAPD (Senescence-Associated Protein Degradation). Ce processus cible des protéines requises pour différentes fonctions cellulaires, incluant la progression du cycle cellulaire, les fonctions mitochondriales et la biogenèse des ribosomes. Ensuite, nos résultats montrent qu’en plus d’inhiber l’établissement de la sénescence, une diminution de la signalisation par les kinases ERK favorise la reprogrammation cellulaire, laquelle permet aux cellules précancéreuses de développer leur tumorigénicité et aux cellules cancéreuses d’acquérir des propriétés attribuables aux cellules souches. Ces observations suggèrent que les mécanismes qui inhibent la voie ERK/MAPK pourraient favoriser l’initiation du cancer, la formation de métastases et la résistance à diverses thérapies. Enfin, nous avons démontré que la metformine, utilisée pour le traitement du diabète, inhibe le facteur de transcription NF-kB. Ce dernier joue un rôle central dans la reprogrammation cellulaire et dans la production de cytokines pro-inflammatoires nocives par les cellules sénescentes. Ainsi, nous émettons l’hypothèse que la metformine pourrait être utilisée en combinaison avec certaines thérapies afin d’éviter les effets secondaires tant d’une inhibition des kinases ERK que d’une hyperactivation. Globalement, les résultats présentés démontrent que l’effet de la voie ERK/MAPK dépend de la force de son activation. Alors qu’une activation modérée peut contribuer à la prolifération de la plupart des cellules, une forte activation induit la sénescence tandis qu’au contraire, une faible activation favorise la reprogrammation des cellules cancéreuses et donc une augmentation de l’agressivité de la tumeur. Cette polyvalence de la voie suggère une certaine prudence face à l’usage des inhibiteurs de la voie ERK/MAPK. Cependant, elle nous motive à travailler au développement de nouvelles stratégies thérapeutiques, lesquelles pourraient inclure la metformine. / The Extracellular Signal-Regulated Kinases (ERK1/2) regulate multiple cellular processes such as proliferation, survival and differentiation. These kinases are the last component of the ERK/MAPK pathway, which is activated in about 30% of all human cancers. Therefore, current thinking proposes that the ERK/MAPK pathway is a critical mediator of tumor progression. However, a steadily growing number of observations suggest that ERK kinases could trigger tumor suppression as well. The first aim of this thesis is to determine how ERK signaling triggers tumor suppression and to try to reconcile these mechanisms with its putative contribution to tumor progression. Since our work has a profound impact on the value of some therapies currently in development, the second aim of the thesis is to propose new strategies to fight cancer. We found that hyperactivation of the ERK kinases induces cellular senescence. Mechanistically, this involves selective proteasome-dependent protein degradation. This “Senescence-Associated Protein Degradation” (SAPD) targets proteins required for several cellular functions, including cell cycle progression, mitochondrial functions and ribosome biogenesis. Furthermore, our results showed that downregulation of ERK signaling not only inhibits the establishment of senescence but promotes cellular reprogramming, thereby allowing precancerous cells to gain tumorigenicity and cancer cells to acquire stem cell-like properties. These results suggest that mechanisms downregulating the ERK/MAPK pathway could promote cancer initiation, metastasis and resistance to multiple therapies. Finally, we demonstrated that the antidiabetic drug metformin targets the transcription factor NF-kB. The latter plays a central role in reprogramming, but also in the generation of deleterious pro-inflammatory cytokines by senescent cells. Hence, we suggest that metformin could be used in combination with other therapies to avoid the side effects of either downregulating or overactivating ERK signaling. Taken together, the results presented in this thesis demonstrate that the outcome of the ERK/MAPK pathway activity depends on signaling strength. While a moderate activation of the pathway may contribute to cell proliferation, a strong activation induces senescence and, conversely, a low activation promotes cancer cell reprogramming. This versatility of the pathway suggests caution with the use of ERK/MAPK pathway inhibitors, but motivates us to develop new therapeutic strategies, which could include metformin.

Autosomal recessive primary microcephaly (MCPH) is a congenital neurodevelopmental disorder characterised by a reduced occipital-frontal head circumference (OFC) of less than -3 SDs below the population mean for age and sex. It is a genetically heterogeneous disorder caused by mutations in one of the following 10 MCPH genes: MCPH1 (microcephalin 1), WDR62 (WD repeat domain 62), CDK5RAP2 (cyclin-dependent kinase 5 regulatory associated protein 2), CASC5 (cancer susceptibility candidate 5), CEP152 (centrosomal protein 152 kDa), ASPM (asp [abnormal spindle] homolog, microcephaly associated [Drosophila]), CENPJ (centromeric protein J), STIL (SCL/TAL1-interrupting locus), CEP135 (centrosomal protein 135 kDa) and CEP63 (centrosomal protein 135 kDa). The MCPH1 (microcephalin 1) gene is located on chromosome 8p23.1. Microsatellite analysis has previously shown LOH at the markers D8S518 and D8S277 flanking the MCPH1 locus in 1/21 oral tumors. Furthermore, LOH at the markers D8S1742 and D8S277 flanking the MCPH1 locus has also been observed in 2/32 hepatocellular carcinomas. MCPH1 has been found to be mutated in breast and endometrial cancers. Additionally, it was found to be downregulated at the transcript level in 19/30 ovarian cancer tissues and the protein level in 93/319 breast cancer tissues. Decreased MCPH1 protein levels are associated with triple negative breast cancers and a lower transcript level of MCPH1 correlates with lesser time for metastasis to occur in breast cancer patients. Interestingly, MCPH1 knockout mice in a null TP53 background show susceptibility to cancer.So far, studies have indicated that MCPH1 is a DNA repair protein. MCPH1 is required for the formation of DNA repair foci, chromatin relaxation, HR and NHEJ. It regulates G1/S and G2/M cell cycle checkpoints. Also, depletion of MCPH1 leads to genomic instability and centrosome amplification. Hence, the defect in the function of MCPH1 can lead to plethora of anomalies including cancer. Based on these observations, we hypothesized that MCPH1 may also function as a tumor suppressor (TS) gene, in addition to its role in the brain development. The purpose of this study was to test if MCPH1 also functions as a TS gene using different approaches in OSCC (oral squamous cell carcinoma). OSCC is the sixth most common type of cancer. It includes the cancer of the lips, anterior 2/3rd of the tongue, buccal mucosa, floor of the mouth, retromolar trigone and gingiva. Despite the advances in the treatment of oral cancer, the five-yr survival rate has not increased. Hence, the effective treatment of OSCC requires the identification of molecular targets to design appropriate therapeutic strategies. LOH, mutations and promoter methylation in tumors are the hallmarks of TS genes. In order to ascertain the TS roles of MCPH1, we carried out LOH analysis in 81 matched blood/normal and tumor oral tissues using D8S1819, D8S277 and D8S1798 markers flanking the MCPH1 locus. The results showed LOH at one or more markers in 14/71 (19.72%) informative samples across the tumor stages from T1 to T4. The entire coding region and the exon-intron junctions of the MCPH1 gene were sequenced for mutations in 15 OSCC samples and 5 cancer cell lines (viz., A549, HeLa, KB, SCC084 and SCC131). In total, three mutations namely c.1561G>T(p.Glu521X), c.321delA(p.Lys107fsX39) and c.1402delA(p.Thr468fsX32) were identified. The expression of MCPH1 was analysed at both the transcript and protein levels by real-time quantitative RT-PCR and immunohistochemistry, respectively, in OSCC samples. MCPH1 was downregulated in 51.22% (21/41) of OSCC samples at the transcript level. The MCPH1 protein was downregulated in 76% (19/25) of the OSCC samples. In order to elucidate if the MCPH1 promoter was methylated in OSCC tissues, we retrieved the MCPH1 promoter from the database TRED (Transcriptional Regulatory Element Database). The promoter was analysed for the presence of CpG islands using the CpG Plot/CpG Report program. Two CpG islands (CpGI and CpGII) were identified within the MCPH1 promoter. Both the CpG islands were analysed for methylation in 40 OSCC samples by COBRA (Combined Bisulfite Restriction Analysis). CpGI showed no methylation in 40 OSCC samples. However, CpGII showed methylation in 4/40 (10%) OSCC samples and the methylation was absent in their corresponding normal oral tissues. To analyse the methylation of the MCPH1 promoter in cancer cell lines, HeLa, KB, SCC084 and SCC131 cells were treated with 5’-2-deoxy azacytidine (AZA), a methyltrasferase inhibitor. HeLa and KB cells did not show any change in the MCPH1 transcript level after the AZA treatment. However, SCC084 and SCC131 cells showed upregulation of MCPH1 after the treatment, suggesting methylation of the MCPH1 promoter. To validate these observations, we examined the methylation status of both the CpG islands in these cell lines. We found methylation of CpGII only in SCC084 cells. HeLa, KB and SCC131 cells showed no methylation of CpGI and CpGII. The results obtained by COBRA in these cell lines were further confirmed by bisulfite sequencing of CpGI and CpGII islands. Further, the upregulation of MCPH1 after azacytidine treatment in SCC131 cells can be attributed to a promoter independent mechanism or due to methylation of the CpG sites not examined by us. To elucidate the biological effects of MCPH1 in a cancer cell line, we generated stable clones overexpressing MCPH1 in KB cells. The results showed that MCPH1 overexpression decreased cellular proliferation, cell invasion, anchorage-independent growth in soft-agar and tumor growth in nude mice. Further, MCPH1 overexpression lead to apoptosis. A low frequency of LOH, mutations and promoter methylation suggested that they might not be the major mechanisms of downregulation of MCPH1 in OSCC. We then speculated that MCPH1 could be regulated by miRNAs. We therefore used five miRNA target prediction softwares to identify miRNAs targeting MCPH1. The programs identified two binding sites for miR-27a within the 5.4 kb region of the 3’-UTR of MCPH1. The luciferase assay showed that both the seed regions of MCPH1 were binding to miR-27a. In addition, transient transfection of the premiR-27a construct in KB cells decreased the protein level of MCPH1. Additionally, in a small panel of 10 OSCC samples, there was a negative correlation between the levels of miR-27a and MCPH1. To the best of our knowledge, this is the first report showing any miRNA regulating the MCPH1 gene. It is important to note that tumor suppressors can serve as potential biomarkers with prognostic value. Hence, we analysed the correlation of the expression levels of MCPH1 with clinico-pathological parameters such as TNM, gender, age and site of the cancer by Fischer’s exact test. No statistical correlation was observed between the transcript or protein levels with any of the clinico-pathological parameters. In summary, the results of the present study have suggested that the primary microcephaly gene MCPH1 shows several hallmarks of TS genes and functions as a tumor suppressor in OSCC, in addition to its role in brain development. We have for the first time shown that miR-27a targets MCPH1 and regulates its level. It is interesting to note that none of the other 10 MCPH genes have been shown to be regulated by any miRNA yet. Our study will be useful in designing novel therapeutic methods for the treatment of OSCC either by overexpression of MCPH1 or reducing the level of miR-27a by an antagomir.