Involvement of Collagen XVII in Pluripotency Gene Expression and Metabolic Reprogramming of Lung Cancer Stem Cells

Abstract

Background: Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms. Methods: The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients. Findings: We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin 5 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients. Interpretation: These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment. Funding Statement: This work was supported by the Ministry of Science and Technology (MOST 106-2314-B-010-028-MY3, MOST 106-2314-B-075-030-MY3, MOST 106-2321-B-039-003) and Taipei Veteran General Hospital (V107C-182, V106C-060, V106C-174). This work was also financially supported by the “Drug Development Center, China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Protocols involving mice were approved by the Institutional Animal Committee of Taipei Veterans General Hospital.