Novel mutations and role of the LKB1 gene as a tumor suppressor in renal cell carcinoma
| Autor: | Oner Sanli, Nejat Dalay, Nur Buyru, Zubeyde Yalniz, Hatice Tigli, Hulya Tigli |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Gene mutation Biology Protein Serine-Threonine Kinases medicine.disease_cause Exon Open Reading Frames AMP-Activated Protein Kinase Kinases Gene expression medicine Humans Genes Tumor Suppressor Neoplasm Metastasis Gene Carcinoma Renal Cell PI3K/AKT/mTOR pathway Aged Neoplasm Staging Mutation TOR Serine-Threonine Kinases RPTOR General Medicine Middle Aged Molecular biology Kidney Neoplasms Tumor Burden Cancer research biology.protein Female Neoplasm Grading RHEB Signal Transduction |
| Zdroj: | Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 35(12) |
| ISSN: | 1423-0380 |
| Popis: | The tumor suppressor LKB1 gene is a master kinase and inhibits mammalian target of rapamycin (mTOR) by activating AMP-activated protein kinase (AMPK) and AMPK-related kinases. LKB1 is a critical intermediate in the mTOR signaling pathway, and mutations of the LKB1 gene have been implicated in the development of different tumor types. Recent evidence indicates that LKB1 alterations contribute to cancer progression and metastasis by modulating vascular endothelial growth factor (VEGF) production. The Ras homolog enriched in brain (RHEB) protein is a component of the mTOR pathway and functions as a positive regulator of mTOR. However, the mechanisms and effectors of RHEB in mTOR signaling are not well known. In this study, we analyzed the expression of RHEB and HIF1α genes in correlation with LKB1 gene mutations. All coding exons and exon/intron boundaries of the LKB1 gene were analyzed by direct sequencing in 77 renal cell carcinoma (RCC) tumors and 62 matched noncancerous tissue samples. In 51.6 % of the patients, ten different mutations including four novel mutations in the coding sequences and six single nucleotide substitutions in the introns were observed. Rheb and HIF1α expression levels were not statistically different between the tumor and corresponding noncancerous tissue samples. However, expression of the Rheb gene was upregulated in the tumor samples carrying the intron 2 (+24 G→T) alteration. Association between the gene expression and tissue protein levels was also analyzed for HIF1α in a subgroup of patients, and a high correlation was confirmed. Our results indicate that the LKB1 gene is frequently altered in RCC and may play a role in RCC progression. |
| Databáze: | OpenAIRE |
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