Abstract
ObjectivesLung cancer is the leading cause of cancer-related deaths worldwide. Overall 5-year survival has shown little improvement over the last decades. Seven in absentia homolog (SIAH) proteins are E3 ubiquitin ligases that mediate proteasomal protein degradation by poly-ubiquitination. Even though SIAH proteins play a key role in several biological processes, their role in human cancer remains controversial. The aim of the study was to document SIAH2 expression pattern at different levels (mRNA, protein level and immunohistochemistry) in human non-small cell lung cancer (NSCLC) samples compared to surrounding healthy tissue from the same patient, and to analyse the association with clinicopathological features.Materials and MethodsOne hundred and fifty-two samples from a patient cohort treated surgically for primary lung cancer were obtained for the study. Genic and protein expression levels of SIAH2 were analysed and compared with clinic-pathologic variables.ResultsThe present study is the first to analyze the SIAH2 expression pattern at different levels (RNA, protein expression and immunohistochemistry) in non-small cell lung cancer (NSCLC). We found that SIAH2 protein expression is significantly enhanced in human lung adenocarcinoma (ADC) and squamous cell lung cancer (SCC). Paradoxically, non-significant changes at RNA level were found, suggesting a post-traductional regulatory mechanism. More importantly, an increased correlation between SIAH2 expression and tumor grade was detected, suggesting that this protein could be used as a prognostic biomarker to predict lung cancer progression. Likewise, SIAH2 protein expression showed a strong positive correlation with fluorodeoxyglucose (2-deoxy-2(18F)fluoro-D-glucose) uptake in primary NSCLC, which may assist clinicians in stratifying patients at increased overall risk of poor survival. Additionally, we described an inverse correlation between the expression of SIAH2 and the levels of one of its substrates, the serine/threonine kinase DYRK2.ConclusionsOur results provide insight into the potential use of SIAH2 as a novel target for lung cancer treatment.
Highlights
Lung cancer continues to be the leading cause of cancer-related mortality worldwide, accounting for nearly 1.4 million deaths annually [1]
We found that SIAH2 protein expression is significantly enhanced in human lung adenocarcinoma (ADC) and squamous cell lung cancer (SCC)
An increased correlation between SIAH2 expression and tumor grade was detected, suggesting that this protein could be used as a prognostic biomarker to PLOS ONE | DOI:10.1371/journal.pone
Summary
Lung cancer continues to be the leading cause of cancer-related mortality worldwide, accounting for nearly 1.4 million deaths annually [1]. Contrary to breast or prostate cancers, in which survival has improved significantly, overall 5-year survival for lung cancer has shown little improvement over the last two or three decades. The relative 5-year survival rate is 11– 15% [2, 3], which means that 90% of patients will die of the disease. The majority of patients present with an advanced disease (stages III and IV), being systemic therapy with chemotherapy and/or radiation therapy the most beneficial treatment modality. Several new molecular therapeutic targets have been described, but their efficiency and clinical impact remains unclear [5]. These data highlights the need of new and more effective therapies
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