Silence of the tumor suppressor miR-34c is implicated in the development of colorectal cancer (CRC). For the past few years, Resveratrol (Res) has been introduced to oncotherapies alone or with traditional chemotherapeutic drugs. However, the study of molecular mechanism involved in the anti-CRC effect of Res is still ongoing. The anti-CRC effect of Res alone or with Oxaliplatin (Oxa) was determined by cell viability assay, soft agar colony formation assay, flow cytometry and real-time cellular analyzer in HT-29 (p53 + ) and HCT-116 (p53 − ) CRC cell lines. Expressions of miR-34c and its targets were detected by qPCR and/or western blot. To evaluate the role of miR-34c in anti-CRC effect by Res alone or with Oxa, miR-34c was up or down-regulated by lentiviral mediation or specific inhibitor, respectively. To investigate how miR-34c was increased by Res, the methylation status of miR-34c promoter was detected by MSP. The tumor bearing mouse model was established by subcutaneous injection of HCT-116 cells to assess anti-CRC effect of Res alone or with Oxa in vivo. IL-6 and TNF-α in xenografts were detected by ELISA. Res inhibited cell viability, proliferation, migration and invasion as well as promoted apoptosis both in HT-29 and HCT-116 CRC cells. The anti-CRC effect of Res was partially but specifically through up-regulating miR-34c which further knocked down its target KITLG; and the effect was enhanced in the presence of p53 probably through inactivating PI3K/Akt pathway. Besides, Res sensitized CRC cells to Oxa in a miR-34c dependent manner. The xenograft experiments showed that exposure to Res or Oxa suppressed tumor growth; and the efficacy was evidently augmented by the co-treatment of Res and Oxa. Likewise, miR-34c level was elevated in xenografts of Res-treated mice while the KITLG was decreased. Finally, Res clearly reduced IL-6 in xenografts. Res suppressed CRC by specifically activating miR-34c-KITLG in vitro and in vivo; and the effect was strengthened in the presence of p53. Besides, Res exerted a synergistic effect with Oxa in a miR-34c dependent manner. We also suggested that Res-increased miR-34c could interfere IL-6-triggered CRC progression.

Macrophage receptor with collagenous structure (MARCO) is a member of the class A scavenger receptor family which is expressed on the cell surface of macrophages. It is well known that MARCO avidly binds to unopsonized pathogens, leading to its ingestion by macrophages. However, the role of MARCO in the recognition and phagocytosis of tumor cells by macrophages remains poorly understood. In this study, we used lentiviral technology to knockdown and overexpress MARCO and investigated the ability of macrophages to phagocytose tumor cells. Our results showed that MARCO expression was correlated with the ability of macrophages to carry on phagocytosis. MARCO knockdown led to significant decreases in the number of engulfment pseudopodia of macrophages and inhibition of the phagocytosis of tumor cells. On the other hand, MARCO overexpression elevated activity of SYK, PI3K and Rac1 in macrophages, which led to changes in macrophage morphology and enhanced phagocytosis by promoting formation of stress fibers and pseudopodia. By Co-IP analysis we showed that MARCO directly binds to the β5 integrin of SL4 tumor cells. In summary, these results demonstrated the important role for MARCO in demonstrated tumor cells uptake and clearance by macrophages.

Mucinous colorectal adenocarcinoma (MCA) patients often a show high risk of malignant potential and a poorer survival rate. Given that the pathological feature and oncobiological characteristics of MCA are correlated with its abundant extracellular mucin2 (MUC2), we paid interest toward investigating the key factor that promotes MUC2 production exposure to highly-activated stem cell factor (SCF)/c-KIT signaling, which we believed to contribute to MCA formation. Long-term azoxymethane and dextran sodium sulfate treatment successfully induced MCA only in wild-type (WT) mice at week 37 and 43, while all c-kit loss-of-function mutant mice (Wads^m/m) developed non-MCA. Significantly, MUC2 and its key transcriptional factor Atonal homologue 1 (Atoh1) were remarkably expressed in MCA mice compared with non-MCA mice. Atoh1 was significantly elevated in colorectal cancer (CRC) cells stimulated by exogenous SCF or overexpressing c-KIT in vitro, while decreased by the blockage of SCF/c-KIT signaling with Imatinib. Furthermore, the maintained Atoh1 protein level was due to the inactive glycogen synthase kinase 3β (p-GSK3β) by virtue of the activated SCF/c-KIT-Protein Kinase B (AKT) signaling. Similar results were obtained from the ONCOMINE database and CRC patients. In conclusion, we suggested that SCF/c-KIT signaling promoted MUC2 production and MCA tumorigenesis by maintaining Atoh1 expression. Therefore, targeting the related key molecules might be beneficial for treating MCA patients.