MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway

Abstract

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) is a predicted oncoprotein that demonstrates tumorigenic activity in vivo; however, the mechanisms involved are unknown. Macrophages are divided into the pro-inflammatory M1 and anti-inflammatory/protumoral M2 subtypes. Tumor cells can induce M2 polarization of tumor-associated macrophages (TAMs) to promote metastasis; but the underlying pathways require to be elucidated. In this study, we detected a positive association between MFHAS1 expression in TAMs and human colorectal cancer (CRC) TNM stage. Supernatant of CT26 murine CRC cells induced MFHAS1 expression in RAW264.7 murine macrophages. Additionally, CT26 supernatant induced the M2 marker CD206 and activated the pro-M2 STAT6 and KLF4 signaling in control but not MFHAS1-silenced RAW264.7 macrophages. Moreover, supernatant of control, but not MFHAS1-silenced macrophages promoted CT26 cell proliferation, migration and epithelial-mesenchymal transition. Compared with control macrophages, MFHAS1-silenced macrophages showed significantly reduced protumoral effects in vivo. Together, these results suggested that CRC cells induce M2 polarization of TAMs through MFHAS1 induction and subsequent STAT6 and KLF4 activation to promote CRC progress. Finally, similar to CT26 supernatant stimulation, peroxisome proliferator-activated receptor-γ (PPARγ) activation by rosiglitazone induced M2 polarization of RAW264.7 macrophages through MFHAS1-dependent pathway. Our results highlight the role of MFHAS1 as a regulator of macrophages polarization and CRC progress.

The Immune-microenvironment Confers Chemoresistance of Colorectal Cancer through Macrophage-Derived IL6

“…It is difficult to establish a standard assay to measure TAMs in different tumors, which may partly explain these inconsistencies in colorectal cancer. Despite the inconsistent results concerning the prognostic role of TAMs in colorectal cancer, recent data showed that TAMs exert tumor-promoting functions by regulating cell growth, metastasis, and drug resistance in colorectal cancer (34)(35)(36)(37)(38). Because the phenotypes of TAMs are highly plastic and associated with tumor stage and their location in TME (33,39,40), we measured the total macrophage infiltration other than M1 or M2 macrophage in representative patients with colorectal cancer to investigate its clinical significance.…”

Fasting inhibits colorectal cancer growth by reducing M2 polarization of tumor-associated macrophages

“…We also explored the relevant signal pathways associated with adenosine regulating of M2 polarization of TAMs. There are different signal pathways involved in polarization of macrophages such as MAPK/JNK, PI3K/AKT and JAK/STAT [ 29 – 31 ]. Here we found that JAK1/STAT3 signal pathway played an important role in M2 polarization of TAMs.…”

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

“…[14] LRRK2 has been implicated in a diverse range of cellular processes, including macroautophagy, cytoskeletal dynamics, and mitochondrial function. [15] Finally MASL1, the least studied of the human ROCO proteins, has functional connections to macrophage polarization [16,17] and erythropoiesis. [18] These proteins also have disease relevance: DAPK1, LRRK1, and MASL1 in cancers, [19–21] while mutations in LRRK2 are a common genetic contributor to familial Parkinson’s Disease (PD) [22] and LRRK2 has been associated with numerous other human diseases.…”