T-box transcription factor Brachyury in lung cancer cells inhibits macrophage infiltration by suppressing CCL2 and CCL4 chemokines

Abstract

Both intra-tumor macrophage and T-box transcription factor Brachyury (T) have been proved to play important roles in tumor progression and metastasis. However, it is still unknown whether T could regulate the infiltration of macrophages. Here, we report that the Brachyury expression in human lung tumors was inversely correlated with the infiltration of macrophages. Brachyury suppressed the capability of human lung cancer cells to attract macrophages. Using PCR array, we found that Brachyury inhibited expression of several chemokines, including CCL2, CCL4, and CXCL10. Accordingly, knockdown of CCL2 and CCL4 in lung cancer cells suppressed macrophage invasion under coculture conditions. Furthermore, we found that Brachyury expression was inversely correlated with CCL2 and CCL4 expression in human lung tumors. Taken together, our findings shed light on the novel role of Brachyury in regulation of macrophage infiltration.

Broadleaf Mahonia attenuates granulomatous lobular mastitis‑associated inflammation by inhibiting CCL‑5 expression in macrophages

“…The results showed that four cytokines, CCL-2, CCL-3, CCL-5 and sTNFR, exhibited significant reductions in expression after BM treatment, and that CCL-5 had the highest inhibition ratio. Mounting evidence records the abilities of CCL-2, 3 and 5 in recruiting macrophages into inflammation sites ( 43 – 45 ), and the present data also revealed that the suppressive effects of BM on NF-κB activity were relieved following the addition of CCL-5, indicating that CCL-5 may be the main molecular target in the anti-inflammatory activity of BM. Previous studies demonstrated that the IKK inhibitor repressed the mRNA levels of CCL-5 by ~81%, and these results indicated that CCL-5 may also act as an upstream factor enhancing NF-κB activity ( 46 ).…”

High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma

“…A recent study demonstrated that Lewis lung carcinoma cells harbor the activating Kras G12C mutation, which upregulates CCL2 production linking cancer‐associated inflammation . A previous study reported that knockdown of CCL2 and CCL4 in lung cancer cells could suppress macrophage invasion under co‐culture conditions . This evidence suggests that lung cancer cell‐derived CCL2 and CCL4 can recruit macrophages into the tumor microenvironment, promoting cancer progression.…”

“…36 A previous study reported that knockdown of CCL2 and CCL4 in lung cancer cells could suppress macrophage invasion under co-culture conditions. 37 This evidence suggests that lung cancer cell-derived CCL2 and CCL4 can recruit macrophages into the tumor microenvironment, promoting cancer progression. In the present study, using antibody array, Western blot, and qRT analyses, we found higher RNA and protein levels of CCL2 and CCL4 in the LUAD than in LUSC microenvironment.…”

Obesity Does Not Exacerbate the Protumorigenic Systemic Environment in Sarcoma Subjects

“…This is particularly relevant given the substantial and clear divergence in serum CCL4 concentrations in sarcoma subjects versus healthy controls (with means of 974 pg/ml versus 28.2 pg/ml, respectively). Prior studies in other tumor models have described CCL4 expression as being either tumor promoting ( 23 – 25 ) or being host protective and associated with prolonged survival ( 26 , 27 ). Therefore, an understanding of the exact role of CCL4 in adult sarcoma is needed before its use as a potential therapeutic target can explored.…”