Hypoxia-Induced PTTG3P Contributes to Colorectal Cancer Glycolysis and M2 Phenotype of Macrophage

Abstract Long noncoding RNAs (lncRNAs) play critical factors in tumor progression and are ectopically expressed in malignant tumors. Until now, lncRNA pituitary tumor-transforming 3, pseudogene (PTTG3P) biological function in colorectal cancer (CRC) further needs to be clarified. qRT-PCR was used to measure the PTTG3P level and CCK-8, glucose uptake, lactate assay, adenosine triphosphate (ATP) assay, extracellular acidification rate (ECAR) assay, and xenograft mice model were adopted to evaluate the glycolysis and proliferation, and macrophage polarization were determined in CRC cells. Xenograft experiments were utilized to analyze tumor growth. Ectopic expression of PTTG3P was involved in CRC and related to dismal prognosis. Through gain- and loss-of-function approaches, PTTG3P enhanced cell proliferation and glycolysis through YAP1. Further, LDHA knockdown or glycolysis inhibitor (2-deoxyglucose (2-DG), 3-BG) recovered from PTTG3P-induced proliferation. And PTTG3P overexpression could facilitate M2 polarization of macrophages. Silenced PTTG3P decreased the level of inflammatory cytokines TNF-α, IL-1β and IL-6, and low PTTG3P expression related with CD8+ T, NK, and TFH cell infiltration. Besides, hypoxia-inducible factor-1α (HIF1A) could increase PTTG3P expression by binding to the PTTG3P promoter region. Hypoxia-induced PTTG3P contributes to glycolysis and M2 phenotype of macrophage, which proposes a novel approach for clinical treatment.