The Role And Mechanism Of HMCES In Non-small Cell Lung Cancer

Lung cancer is the most common type of malignant cancer,and it is also the leading cause of cancer deaths worldwide.Approximately 85% of patients have a group of histological subtypes collectively known as non-small cell lung cancer(NSCLC).A large proportion of NSCLC patients present with metastatic disease at the time of diagnosis and may not be suitable for surgical treatment.Therefore,it is urgent and conducive to identify and investigate the factors involved in the development of NSCLC.HMCES(5-hydroxymethylcytosine binding,embryonic stem cell specific-protein),is located on chromosome 3 and encodes a protein that was initially identified in mouse embryonic stem cells as a specific binding protein of 5-hydroxymethylcytosine.However,HMCES has recently been reported as a DNA repair protein,which covalently cross-links to DNA at abasic sites in single-stranded DNA and maintains genome stability.Through genome-wide transcriptome analysis,we found that HMCES expression was significantly up-regulated in many cancer types(e.g.,NSCLC,cervical cancer,lymphoma,and pancreatic cancer),indicating that HMCES may function in the occurrence and development of cancer.However,the role of HMCES in NSCLC has not yet been reported.In this study,we investigated the function and mechanism of HMCES in the development of NSCLC.Analysis of HMCES expression levels in the TCGA(The Cancer Genome Atlas)datasets reveals that HMCES is highly expressed in NSCLC tissues.Comparison of HMCES expression levels between tumors and normal tissues in 85 clinical NSCLC patients revealed that both m RNA and protein levels of HMCES were significantly higher in tumors.Elevated HMCES expression was correlated with poor survival of NSCLC patients.In addition,patients with elevated HMCES expression showed more advanced stages of NSCLC.By overexpression and knockdown of HMCES in NSCLC cell lines,we found that HMCES depletion inhibited cell proliferation,migration,and invasion.Similarly,HMCES depletion also inhibited tumor growth and metastasis in our in vivo models.These results suggest that HMCES contributes to the development of NSCLC.Mechanismly,HMCES knockdown resulted in genome instability,G2/M cell cycle arrest,and thus inhibition of cell proliferation.We further performed tramscriptome analysis comparing HMCES-knockdown and control NSCLC cells.The differentially expressed genes we identified were enriched in DNA repair,DNA replication,cell cycle,cell-substrate adhesion,extracellular matrix organization,and actin cytoskeleton organization pathways.Moreover,the epithelial-mesenchymal transition(EMT)process was remarkably inhibited upon HMCES knockdown,which may lead to the reduced migration and invasion of NSCLC cells.Taken together,our results revealed that HMCES was involved in the development of NSCLC by affecting NSCLC cell proliferation,migration and invasion.HMCES may potentially serve as a biomarker for the diagnosis and prognosis of NSCLC.Moreover,silencing HMCES or using small molecule inhibitors of HMCES may be an effective intervention for NSCLC.Thus,our study provides a promising target for NSCLC treatment.