RETRACTED ARTICLE: miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization

Abstract

Background: Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial-mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration. Methods: An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo. Results: An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization. Conclusions: miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.

Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression

“…Moreover, Bergenfelz et al observed that Wnt5a was mainly located in CD163 + TAMs in breast cancer and could induce a tolerogenic phenotype of macrophages (24). Based on the above studies and our previous results (8,9), we speculated that Wnt5a might induce M2 polarization of TAMs to promote tumor development in CRC.…”

“…Circulating tumor cells (CTCs) were captured, isolated, and identified by a novel CTCBIOPSY method as reported by our previous study (8,9,26). Briefly, 1 ml of blood of mice was first diluted with 4 ml of 0.9% physiological saline and then totally transferred to ISET tubes with an 8-µm diameter aperture membrane.…”

“…We demonstrated that TAMs, especially M2 subtype, induced epithelial-mesenchymal transition (EMT) of cancer cells to promote circulating tumor cellmediated colorectal cancer (CRC) metastasis (8). Meanwhile, we also found that EMT-programmed cancer cells could remodel the tumor microenvironment and activate TAMs to M2 phenotype (9), thereby facilitating tumor progression and metastasis (10,11). Therefore, M2-like TAMs might be critical players in the crosstalk between cancer cells and their microenvironment (10,12).…”

Integrated Analysis Identifies a Nine-microRNA Signature Biomarker for Diagnosis and Prognosis in Colorectal Cancer

“…Only original experimental studies to screen miRNAs that were differentially expressed (DE) between CRC and ANT in at least 40 human samples were included. Selection criteria, probe annotation, and data normalization were the same as described in previous reports (Sun et al, 2017a,b;Lin et al, 2019).…”

“…A single model incorporating multiple biomarkers demonstrates improved performance and stability of prognostic value (Agesen et al, 2012;Marisa et al, 2013). However, further validation is still needed for the implementation of these miRNAs in standard CRC clinical practice, and the underlying mechanism remains to be elucidated (Huang et al, 2017;Lin et al, 2019).…”