Dynamics of K-RAS and AKT Palhuag in oral premalignant heirs and grade 11 OSCC.

Abstract

INTRODUCTION: Lesions like leukoplakia, erythroplakia, oral erosive lichen planus and premalignant conditions like oral submucous fibrosis are few of the oral premalignant lesions/conditions which have high prevalence in Pakistan. Oral squamous cell carcinoma may arise from premalignant lesions / conditions of the oral cavity and sometimes it develops denovo. Both are significant health problems influenced by different predisposing factors and are genetic diseases in which the genes that control cell growth and apoptosis are mutated, allowing cells to acquire the ability to invade and metastasize. Earlier diagnosis of these lesions results in better outcome.The clinical and histological features alone cannot accurately predict whether dysplastic alterations and potentially premalignant lesions of the oral mucosa will remain stable, regress or progress to malignancy. Literature supports that Ras/PI3K/Akt pathways are involved in the progression of normal oral mucosa to premalignant lesions and subsequently to oral cancer. Early diagnosis by identifying genetic alterations could improve clinical outcome by potentially minimizing the need for interventions like surgery, radiotherapy and chemotherapy. In our population we have different genetic make-up; different pre-disposing factors and ethical norms so that we can only take a guideline from the published literature but cannot just apply it in letter and spirit. MATERIALS AND METHODS: This study was conducted on a sample of 53 patients reported at different hospitals in Lahore. RESULTS: Results of this study indicate that p53 levels were expressed more in oral premalignant lesions that is 0.05+0.05 and then its level shows a fall with advancement in tumor grade to an expression level of 0.02 +0.00. We also document that Akt levels shows a rise from premalignant lesions to grade II. (Akt1: Premalignant lesions 0.06 + 0.01 & moderately differentiated Grade II OSCC 0.12 + 0.03; Akt 2: Premalignant lesions 0.03 +0.00 & moderately differentiated Grade II OSCC 0.13 + 0.03and Akt 3: Premalignant lesions 0.02 +0.00 & moderately differentiated Grade II OSCC 0.06 + 0.01. KRas expression also increases as the grade of the cancer increases (premalignant lesions 0.02 +0.02 & Grade II OSCC 0.17 +0.01). Similarly, there is modulation in NF-κB and ERK in premalignant lesions and moderately differentiated cancer cells. Both showed increased expression level with proliferation of the tumour cells (NF-κB1/2 in premalignant lesions 0.02 +0.00 and in moderately differentiated OSCC tissues. NF-κB1 is 0.05+0.01 and NF-κB2 is 0.06+0.01 whereas ERK1/2 in premalignant lesions is 0.02+0.00 while in moderately differentiated OSCC tissues it was seen to be 0.12+0.02. 1 The phosphoproteins like mTOR, AktT, IGF-1R ,and RpS6 expressed in both and showed continues increase from oral premalignant lesions to grade II OSCC samples .The proteins like GSK3α and GSK-3β showed no change in oral premalignant lesions but decreased in grade II OSCC samples. Whereas PTEN, TSC2, IRS1 and IR proteins showed gradual decrease from premalignant lesions to grade II OSCC samples. P70S6K showed no change in oral premalignant lesions whereas two times rise was seen in grade II OSCC samples. CONCLUSION: Our study revealed that Akt/Kras pathway is significantly activated in oral premalignant lesions and remains activated in moderately differentiated OSCC. Blocking this pathway at the level of premalignant lesions may help to decrease the chances of progression into oral squamous cell carcinoma.Akt activation along with Kras is a significant prognostic indicator for OSCC and may provide a new method of treatment of OSCC.