Abstract
Simple SummaryThe penetration of various cell types into the tumor microenvironment plays an important role in cancer progression, including metastasis. SFMBT2, an epigenetic factor, is downregulated in metastatic prostate cancer. The aim of the current study is to evaluate the role of SFMBT2 in regulating cell penetration into the prostate cancer microenvironment. Downregulation of SFMBT2 promotes infiltration of preadipocytes and TAMs by up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression. Expression of CXCL8, CCL2, CXCL10, and CCL20 is dependent on NF-κB activation in prostate cancer cells expressing low levels of SFMBT2. Moreover, increased IL-6 from infiltrated preadipocytes and TAMs further enhance migration and invasion of prostate cancer cells. Thus, SFMBT2 could be used as a novel biomarker and target for prostate cancer treatment.Infiltration of diverse cell types into tumor microenvironment plays a critical role in cancer progression including metastasis. We previously reported that SFMBT2 (Scm-like with four mbt domains 2) regulates the expression of matrix metalloproteinases (MMPs) and migration and invasion of cancer cells in prostate cancer. Here we investigated whether the down-regulation of SFMBT2 regulates the infiltration of preadipocytes and tumor-associated macrophages (TAMs) in prostate cancer. We found that the down-regulation of SFMBT2 promotes the infiltration of preadipocytes and TAMs through up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression in prostate cancer. Expression of CXCL8, CCL2, CXCL10, and CCL20 was also elevated in prostate cancer patients having a higher Gleason score (≥8), which had substantially lower SFMBT2 expression. We also found that the up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression is dependent on NF-κB activation in prostate cancer cells expressing a low level of SFMBT2. Moreover, increased IL-6 from infiltrated preadipocytes and TAMs promoted migration and invasion of prostate cancer cells expressing a low level of SFMBT2. Our study may suggest that SFMBT2 a critical regulator for the infiltration of preadipocytes and TAMs into the prostate tumor microenvironment. Thus, the regulation of SFMBT2 may provide a new therapeutic strategy to inhibit prostate cancer metastasis, and SFMBT2 could be used as a potential biomarker in prostate cancer metastasis.
Highlights
Prostate cancer is the second most commonly diagnosed cancer in men over the age of 65 in the developed world
We previously reported that down-regulation of Scm-like with four MBT domains protein 2 (SFMBT2) promotes prostate cancer metastasis through the up-regulation of matrix metalloproteinases (MMPs) and that expression level of SFMBT2 inversely correlates with the prognosis of prostate cancer patients such as invasion and metastasis [26]
Given that infiltration of adipocytes or macrophages into the tumor microenvironment contributes to prostate cancer progression [27,28], we further investigated whether SFMBT2 regulates the expression of chemokines, which are linked to cell infiltration
Summary
Prostate cancer is the second most commonly diagnosed cancer in men over the age of 65 in the developed world. Tumor microenvironment surrounding cancer cells is mainly composed of normal and nonreactive stromal cells including fibroblasts, myofibroblasts, neuroendocrine cells, adipose cells, and immune cells [3]. Cancer cells change their microenvironment by extracellular matrix (ECM) remodeling and the secretion of cytokines, chemokines, and growth factors in either or both an autocrine and paracrine manner [4]. Tumor-associated macrophages (TAMs) are present in the tumor microenvironment and affect prostate cancer progressions such as angiogenesis, metastasis, immune suppression, and drug resistance [15,16]. M1 macrophages (classically activated) produce TNF-α, IFNγ, IL-12, and IL-23 and have pro-inflammation functions, M2 TAMs contribute to immune suppression, tumor growth, and metastasis via secretion of IL1β, IL-6, CXCL8, and VEGF [16,17,18,19]
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