Abstract
Drug resistance remains a serious issue of clinical importance and is a consequence of cancer stemness. In this study, we showed that the level of Aldolase A (ALDOA) expression is significantly associated with the IC50 value of chemotherapy drugs in lung cancer. Our data revealed that ALDOA overexpression resulted in a significant increase of lung tumor spheres. The use of ingenuity pathway analysis (IPA) resulted in the identification of POU5F1 (Oct4) as the leading transcription factor of ALDOA. We observed high expression of ALDOA, Oct4 and stemness markers in collected spheroid cells. DUSP4 and TRAF4 were confirmed as major downstream targets of the ALDOA-Oct4 axis. Knockdown of these molecules significantly decreased the stemness ability of cells. In addition, we investigated whether miR-145 targets the 3′-UTR of Oct4 and is regulated by ALDOA due to the involvement of ALDOA in glycolysis and metabolic reprogramming. Furthermore, we constructed several mutant forms of ALDOA that disrupted its enzymatic activity and showed that they still induced significant in vitro sphere formation and in vivo tumorigenicity. These results demonstrated that ALDOA-mediated spheroid formation is independent of its enzymatic activity. In the clinical component, we also showed that the combination of ALDOA and TRAF4 or DUSP4 is positively correlated with poor overall survival in a xenograft model and cancer patients through immunohistochemical analyses. The results of our study revealed novel functional roles of ALDOA in inducing cancer stemness via the inhibition of miR-145 expression and the activation of Oct4 transcription. These findings offer new therapeutic strategies for modulation of lung cancer stemness to enhance chemotherapeutic responses in lung cancer patients.
Highlights
The recurrence and metastasis of malignant tumors lead to poor outcomes in patients and are important issues in the clinical setting[1]
We proposed that glycolysis-associated genes may trigger the metabolic reprogramming of sphere formation and drug resistance in lung cancer
We analyzed the expression of glycolysis-associated genes from several in silico studies, with our results demonstrating that Aldolase A (ALDOA) plays a unique role and correlates with lung cancer stemness
Summary
The recurrence and metastasis of malignant tumors lead to poor outcomes in patients and are important issues in the clinical setting[1]. Cancer stem cells are an important issue in cancer treatment. Cancer stem cells are viewed as Official journal of the Cell Death Differentiation Association. Chang et al Cell Death and Disease (2020)11:195 stem cells to prolong patient survival and overcome cancer metastasis. Epithelialmesenchymal transition (EMT) is important in the initiation of metastasis of cancer stem cells[9]. Cancer stem cells depend on their specific abilities and on several events to support and maintain the environment and conditions for these cells. The metabolic events of cancer stem cells demonstrate their unique roles, depending on the various cancer types[14]. Liver and breast cancer stem-like cells (CD133+/CD49f+ and CD44+CD24lowEPCAM+, respectively) use a glycolytic pathway rather than OXPHOS17,18. We propose that glycolytic enzymes play a key role in regulating cancer stemness-related factors or metabolite production to promote cancer stemness
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