Abstract
Prostate cancer (PCa) is a major health problem in males. Metastasis-associated with lung adenocarcinoma transcript-1 (MALAT1), which is overexpressed in PCa tissue, is associated with physiological and pathological conditions of PCa. M2 macrophages are major immune cells abundant in the tumor microenvironment. However, it remains unknown whether M2 macrophages are involved in the effects or not, and molecular mechanisms of MALAT1 on PCa progression have not yet been comprehensively explored. Here we reported that, M2 macrophages (PMA/IL-4 treated THP1) induced MALAT1 expression in PCa cell lines. Knockdown MALAT1 expression level in PCa cell lines inhibited cellular proliferation, invasion, and tumor formation. Further mechanistic dissection revealed that M2 macrophages secreted IL-8 was sufficient to drive up MALAT1 expression level via activating STAT3 signaling pathway. Additional chromatin immunoprecipitation (ChIP) and luciferase reporter assays displayed that STAT3 could bind to the MALAT1 promoter region and transcriptionally stimulate the MALAT1 expression. In summary, our present study identified the IL-8/STAT3/MALAT1 axis as key regulators during prostate tumorigenesis and therefore demonstrated a new mechanism for the MALAT1 transcriptional regulation.
Highlights
Prostate cancer (PCa) is a major health problem in men
This study demonstrated that Metastasis-associated with lung adenocarcinoma transcript-1 (MALAT1) overexpression modified by M2 macrophages promoted prostate tumorigenesis via STAT3/MALAT1 pathway
The expression of macrophages surface marker CD68 and M2 macrophages surface marker CD206 increased dramatically in THP-1 cells, implying that THP-1 cell treated with PMA/IL-4 appeared to successfully differentiate into M2 macrophages (Figure 1A)
Summary
Therapeutic progress in PCa includes the approval of radiation therapy and either androgen-deprivation therapy or anti-androgen therapy prolongs survival among some patients with an intact prostate [1]. Despite these therapeutic advances, PCa remains the second leading cause of morbidity and is the third leading cause of male cancer death in the western world [1,2,3]. Many groups of stromal cells, including angiogenic vascular cells, infiltrating immune cells, and cancer-associated fibroblastic cells, have been demonstrated infiltrating in TME [9,10]. Thorpe and colleagues certified that stromal cells produced the IL-8 into the PCa environment and increasing the metastatic properties of PCa cells [17]
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