Metastasis is the main cause of death in colon cancer patients. RBP-Jκ, which is the main transcription mediator of Notch signaling, is involved in colon cancer development but its function in colon cancer metastasis is still unclear. Here we aimed to find out the function of RBP-Jκ in colon cancer metastasis and its underlying mechanisms of modulating the interaction between colon cancer cells and tumor- associated macrophages (TAMs).
Cell migration, invasion and epithelial to mesenchymal transition (EMT) were used to reflect cell metastasis ability. A oc-culture system was adopted to research the mutual regulation between colon cancer cells and TAMs. Gain- and loss-of-function experiments and TGF-β/Smad3 pathway activator and inhibitor were used to determine the underlying mechanisms of RBP-Jκ and TAMs in regulating colon cancer metastasis in vitro and in vivo. RNA sequencing was performed to find out the regulating factor between colon cancer cell and TAMs. RBP-Jκ and E-cadherin expression and TAMs infiltration were examined in 201 colon cancer patients by immunohistochemical assay and were analyzed combined with clinical parameters.
RBP-Jκ and TAMs promoted colon cancer cell metastasis through the TGF-β/Smad3 pathway and secreting of TGF-β, respectively. RBP-Jκ in colon cancer cell facilitated TAMs to secret TGF-β through secreting CXCL11. RBP-Jκ and E-cadherin was highly expressed in colon cancer tissues and para-tumor tissues, respectively. And there are more TAMs infiltrated in colon cancer tissues. RBP-Jκ expression and TAMs infiltration were negatively associated with E-cadherin expression and overall survival and positively associated with metastasis. RBP-Jκ and E-cadherin expression and TAMs infiltration were independent prognostic factors in colon cancer patients.
Our research demonstrated that colon cancer cells with high RBP-Jκ expression secreted CXCL11 to enhance TGF-β secretion of TAMs which facilitated colon cancer metastasis. RBP-Jκ exrpression and TAMs infiltration were associated with colon cancer metastasis and acted as prognostic factors.
Clinical trial identification
Legal entity responsible for the study
National Natural Science Foundation of China (No. 81502099); Key laboratory of tumor precision medicine open project of Shaanxi province (No. KLTPM-SX2018-B3); The scientific research fund of the first affiliated hospital of Xi’an Jiaotong University (2018MS-06).
All authors have declared no conflicts of interest.