The Role of N۱۱۶S Mutation in KRAS Gene and Its Regulation by Hsa- miR- ۵۵۸۶-۵p in Lung Adenocarcinoma (LUAD)

Lung adenocarcinoma (LUAD) is a subtype of non-small cell lung cancer (NSCLC) and the most common type of lung cancer globally. LUAD originates from glandular cells and is known for its aggressive nature. The prognosis is poor, especially in advanced stages where genetic mutations significantly drive tumor progression. A key gene involved in LUAD is KRAS, with mutations often leading to abnormal cell growth and survival. Body KRAS Gene Expression in LUAD In this study, The data were analysed by the GEO dataset GSE ۱۹۸۰۴ and found that KRAS expression is significantly increased in LUAD (Adj. p-value = ۷.۱۳E-۰۳, Log FC = ۰.۰۸۰۱۵۲). Results from GEPIA۲ and ENCORI further confirmed the overexpression of KRAS in tumor tissues compared to healthy samples (Fold Change = ۱.۷۵, FDR = ۱.۹E-۸, p-value = ۳.۱E-۹), highlighting the critical role of KRAS in LUAD. Signaling Pathways in LUAD The KRAS gene plays a central role in several key signaling pathways regulating cell growth and survival, including the Non-Small Cell Lung Cancer (NSCLC) pathway, involving the MAPK/ERK and PI۳K/AKT pathways. KRAS mutations in the MAPK/ERK pathway increase cell division, while activation of the PI۳K/AKT pathway prevents cell death. These changes contribute to LUAD progression by promoting rapid tumor growth and resistance to cell death. Results N۱۱۶S Mutation in P۰۱۱۱۶ Protein Mutation analysis identified the N۱۱۶S mutation in the P۰۱۱۱۶ protein, the product of the KRAS gene, where asparagine (N) is replaced with serine (S) at position ۱۱۶. This mutation was found in the dbSNP database. Structural analysis from the HOPE server shows that serine is smaller and more hydrophobic than asparagine, which leads to the loss of key interactions with ligands such as GNP and disrupts hydrogen bonds in the protein. This may cause misfolding of the P۰۱۱۱۶ protein, leading to continuous activation of signaling pathways and enhancing cancer progression. Regulation of KRAS by miRNA Hsa-miR-۵۵۸۶-۵p Post-translational regulation of KRAS by miRNAs is another factor influencing its expression. Hsa-miR-۵۵۸۶-۵p, identified through the miRWalk database (binding=۱, seed=۱, energy=-۱۴.۹, position=۳'UTR), interacts with KRAS mRNA and may inhibit its translation. miRNAs inhibit specific target mRNAs, and in this case, Hsa-miR-۵۵۸۶-۵p acts as a potential inhibitor of KRAS. Disruption in its expression may lead to increased KRAS levels, contributing to LUAD progression. Conclusion The N۱۱۶S mutation in the P۰۱۱۱۶ protein plays a key role in LUAD by altering the structure of KRAS and affecting important cancer-related signaling pathways such as MAPK/ERK and PI۳K/AKT. Additionally, Hsa-miR-۵۵۸۶-۵p is a regulator of KRAS, and its altered activity may contribute to cancer development. Understanding these mechanisms provides valuable insights for developing therapies targeting KRAS mutations and miRNA interactions in LUAD.

کلیدواژه ها:

LUAD Cancer ، KRAS Gene ، N۱۱۱۶S Mutation ، Hsa-miR-۵۵۸۶-۵p-Signaling Pathway in NSCLC