MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

Abstract

Cellular interactions in the tumor microenvironment influence neoplastic progression in pancreatic ductal adenocarcinoma. One underlying mechanism is the induction of the prognostically unfavorable epithelial-mesenchymal-transition-like tumor budding. Our aim is to explore the expression of microRNAs implicated in the regulation of tumor budding focusing on the microenvironment of the invasive front. To this end, RNA from laser-capture-microdissected material of the main tumor, tumor buds, juxta-tumoral stroma, tumor-remote stroma, and non-neoplastic pancreatic parenchyma from pancreatic cancer cases with (n=7) and without (n=6) tumor budding was analyzed by qRT-PCR for the expression of a panel of miRNAs that are known to be implicated in the regulation of epithelial-mesenchymal transition, including miR-21, miR-183, miR-200b, miR-200c, miR-203, miR-205, miR-210, and miR-217. Here we show that at the invasive front of pancreatic ductal adenocarcinoma, specific microRNAs, are differentially expressed between tumor buds and main tumor cells and between cases with and without tumor budding, indicating their involvement in the regulation of the budding phenotype. Notably, miR-200b and miR-200c were significantly downregulated in the tumor buds. Consistent with this finding, they negatively correlated with the expression of epithelial-mesenchymal-transition-associated E-cadherin repressors ZEB1 and ZEB2 in the budding cells (P<0.001). Interestingly, many microRNAs were also dysregulated in juxta-tumoral compared to tumor-remote stroma suggesting that juxta-tumoral stroma contributes to microRNA dysregulation. Notably, miR-200b and miR-200c were strongly downregulated while miR-210 and miR-21 were upregulated in the juxta-tumoral vs tumor-remote stroma in carcinomas with tumor budding. In conclusion, microRNA targeting in both tumor and stromal cells could represent a treatment option for aggressive pancreatic cancer.

Correlation between FAK and EGF-Induced EMT in Colorectal Cancer Cells

“…However, there have been few reports on miR-217 thus far, and only a small number of researchers have conducted relevant studies. For example, miR-217 is expressed in breast cancer, leukemia [19], lung cancer [20], gastric cancer [21,22], colorectal cancer [23][24][25], and pancreatic cancer [24][25][26][27][28][29]. It exhibits low expression in gastric cancer and is significantly downregulated in colorectal cancer [6].…”

MicroRNA‑874 inhibits proliferation and invasion of pancreatic ductal adenocarcinoma cells by directly targeting paired box 6

“…A large number of studies have shown that many miRNAs are dysregulated in PDAC, and alterations in their expression levels may affect the onset and progression of PDAC (24)(25)(26). Therefore, the expression patterns, biological functions and associated molecular mechanisms of miRNAs in PDAC must be elucidated for the development of novel therapeutic methods.…”

MicroRNA-183 in Cancer Progression

“…In malignant epithelial cells, ZEB1 acts as an activator of EMT, triggering the phenotype transformation of epithelial cells to mesenchymal cells [18]. Studies found that miR-183 was able to target ZEB1 [19]. MiR-183 represses EMT through the regulating of ZEB1, overexpression of miR-183 results in the change of cells from mesenchymal to epithelial.…”