H-Ras mutation modulates the expression of major cell cycle regulatory proteins and disease prognosis in oral carcinoma

Abstract

Activating mutations of the Ras is a moderately frequent event in oral carcinogenesis in Indian patients. Ras pathway has essential roles in regulation of various phases of the cell cycle, especially at G 1 phase. Despite a large body of in vitro evidence, the multidimensional interaction between mutated Ras pathway and G 1 cell cycle regulatory proteins in tumours in vivo is poorly determined. In the present study, DNA samples were screened for mutations in hot spot exons of B-Raf and hot spot codons 12, 13 and 61 of H-, K-and N-Ras by PCR-SSCP. Mutations were confirmed by direct sequencing. Expression of G 1 cell cycle regulatory proteinscyclin D1, CDK4, Rb, p53, p16 and p21 and proliferation marker PCNA was analysed immunohistochemically. The results revealed the absence of B-Raf mutations in oral carcinoma in spite of 12.5% of the samples showing H-Ras mutation. The H-Ras mutant cases showed significantly low cyclin D1 (P ¼ 0.027) and CDK4 (P ¼ 0.046) expression and overexpression of Rb (P ¼ 0.011) and p16 (P ¼ 0.026). H-Ras mutant carriers also had significantly high recurrence-free survival (P ¼ 0.033). In summary the present study demonstrated an epistatic interaction between H-Ras mutation and G 1 cell cycle regulatory proteins in vivo. H-Ras mutation, thus, defines a molecular subtype of oral carcinoma with favourable outcome and unique biology.

Ras in Cancer and Developmental Diseases

“…Finally, H-ras and N-ras mutations have been found in neck and head cancer, where H-Ras overexpression has been also described 143 (Sanger Catalogue of Somatic Mutations in Cancer). In this case, the Ras alterations may be associated with better prognosis, as some reports described better survival rates for patients carrying H-ras mutations in oral cancer 144 and overexpression of WT H-Ras in squamous cell carcinomas of the head and neck. 145…”

PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D

“…Mutated H-Ras is associated with elevated expression of key cell cycle regulatory proteins such as cyclin D1 and cdk4 in in vivo models of oral squamous cell carcinoma of the head and neck region (HNSCC) (Sathyan et al 2007). Cordova-Alarcon et al .…”

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

“…Another way of considering this issue involves defining the temporal sequence of genetic lesions that drive oncogenesis, and thus to infer the sequential downstream interactive effect(s) of each lesion on other as-yet-unmutated regulatory genes. 69 Indeed, increasing evidence supports the importance of such epistatic processes for mammalian cancer development 24,[70][71][72][73] and, perhaps, also for transgenerational carcinogenesis. 6,74 The central finding of the present study is the unanticipated insight that the structural and functional attributes of GKs and POs-when compared with control subgroups of CT cancer suppressor genes and functionally unrelated but developmentally important HD genes-are strikingly similar, as indicated by congruences of evolutionary rate, expression level and breadth, gene length and methylation-dependent mutation confirmed by logistic regression and C-statistics.…”

“…[19][20][21][22] These observations suggest that a dynamic balance exists between expression thresholds of opposing genes within the same network, 23 and that abnormal perturbation of one part of the network could possibly select for normal GK hyperfunction. 24 Such apparent bifunctionality may be explained by epistasis, a concept, which teaches that the function of a given gene is not invariant but rather depends upon the genetic background. 25 In the above example, a possible explanation is that GK protein overexpression may be not only tolerated but also selected in the presence of a block affecting heterologous TSGs.…”