Abstract
Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.
Highlights
Testicular germ cell tumors (TGCTs) are one of the most frequent solid tumors of adolescents and young adult males, which approximately account for 8.9% of tumors among 20–39 year-old males worldwide in 20121,2
We further examined the miR-125b level in normal adult testicular tissues, TGCT tissues, and tumor cell line (NCCIT and NT2) xenografts using qRT-PCR
These findings indicated that miR-125b in embryonic carcinoma was mainly repressed by epigenetic modifications, including DNA methylation, histone modifications and reactive oxygen species (ROS) (Fig. 1h)
Summary
Testicular germ cell tumors (TGCTs) are one of the most frequent solid tumors of adolescents and young adult males, which approximately account for 8.9% of tumors among 20–39 year-old males worldwide in 20121,2. Seminoma is highly similar to primordial germ cells, while embryonic carcinoma is malignant counterparts of embryonic stem cells[4]. Most cancer research has focused upon intrinsic properties of tumor cells (e.g., proliferation, apoptosis) and corresponding therapeutics are directed against these tumor cells. Targeting of tumor cells is not equivalent to targeting of tumor tissues. Advances in cancer research have emphasized that tumor cells display extensive and dynamic cross-talk with the neoplastic microenvironment[8,9,10,11]. Tumor microenvironment is highly heterogeneous, mainly containing
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