One-carbon metabolism in lung cancer

by Sha Yao
Doctoral thesis
Date of Examination:2020-11-11
Date of issue:2020-10-26
Advisor:Prof. Dr. Philipp Ströbel
Referee:Prof. Dr. Volker Ellenrieder
Referee:Prof. Dr. Wolfgang Brück
Persistent Address: http://dx.doi.org/10.53846/goediss-8273

 

 

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Abstract

English

One-carbon metabolism (1CM) plays a central role in cell proliferation and an elevated activity is accounted for the progression of several cancer types. Increased 1CM is a known risk factor for lung cancer and the anti-folate pemetrexed is one of the current standard first-line therapies for non-operable pulmonary adenocarcinoma. The underlining mechanism, the expression and the function of 1CM enzymes in the development and progression of lung cancer remain to be explored. Here, we investigated the 1CM key enzymes MTHFD2, PGDH3, SHMT2, MTHFD1 and TYMS in 323 human lung cancer tissues samples for expression and clinical relevance. Functional analyses for proliferation and chemoresistance of the five 1CM genes were performed in vitro in five adenocarcinoma (AC), five squamous cell lung cancer (SQCLC) and five small cell lung cancer (SCLC) cell lines cell. MTHFD2 expression correlated with a shorter overall survival, pathological grade and lymph statue in AC and with an increased chemoresistance against pemetrexed in cell lines. Knockdown of the 1CM enzymes resulted in decreased cell growth in most and especially in KRAS mutated pulmonary adenocarcinoma cell lines. Our study reveals the importance of one-carbon metabolism in lung cancer progression and proposes MTHFD2 as an independent prognostic marker and a promising anticancer target specially in K-Ras mutated pulmonary adenocarcinoma with no targeted therapy options.
Keywords: One-carbon metabolism, MTHFD2, pemetrexed, lung cancer, chemoresistance; One-carbon metabolism, MTHFD2, pemetrexed, lung cancer, chemoresistance
 
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