Abstract
The complex interaction between tumor-associated macrophages (TAMs) and tumor cells through several soluble factors and signaling is essential for colorectal cancer (CRC) progression. However, the molecular mechanism involved remains elusive. In this study, we demonstrated that MMP1 derived from TAMs markedly facilitated colon cancer cell proliferation via accelerating cell cycle transition from G0/G1 to S and G2/M phase. Moreover, exogenous MMP1 activated cdc25a/CDK4-cyclin D1 and p21/cdc2-cyclin B1 complexes through altering c-Myc and ETV4. Mechanistic studies indicated that inhibition of PAR1 or blockage of MAPK/Erk signaling eliminated the proliferation induced by exogenous MMP1 in vitro and in vivo. In addition, ETV4 could bind to the promoter of MMP1 and activate MMP1 transcription, which confirmed the MMP1/ETV4/MMP1 positive feedback. Altogether, our study identified a cytokine paracrine manner between colon cancer cells and TAMs. MMP1/PAR1/Erk1/2/ETV4 positive feedback loop may represent to be a therapeutic target and prognostic marker in CRC.
Highlights
Colorectal cancer (CRC) ranks the second leading cause of cancerrelated death [1]
tumor-associated macrophages (TAMs) enhanced the proliferation of colon cancer cells For activated macrophage (TAMs) induction, U937 cells were treated with PMA (10 ng/mL) and IL-4 (10 ng/mL) (Fig. 1A)
MMP1 altered the expression of cell cycle-related gene through c-Myc and ETV4 To further elucidate the potential mechanism of MMP1induced proliferation of colon cancer cells, we examined the expression of several cell cycle-related genes by RT-PCR and western blotting analysis
Summary
Colorectal cancer (CRC) ranks the second leading cause of cancerrelated death [1]. ~1,800,000 new cases are diagnosed as CRC every year. Great progress has been achieved in early detection and multimodality treatment of CRC [2, 3], most advanced CRC patients have a poor prognosis. Distant metastasis and relapse are the main cause of death for CRC patients [4, 5]. Emerging evidence confirms that the tumor microenvironment (TME), characterized by the interaction between tumor cells and the host, exerts a pivotal influence on tumor development and progression [6]. Therapeutic strategies targeting TME might complement traditional chemotherapy and enhance anti-tumor effect [7]
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