HOXC6 Promotes Metastasis In Right-sided Colon Cancer

BackgroundColorectal cancer?CRC?is one of the most common digestive tract malignant tumors,its incidence and mortality ranks third among all malignant tumors worldwide^[1].In recent years,more and more studies found that the left-and right-sided colon cancer?LCC and RCC?differ greatly in embryology,epidemiology,molecular characteristics,and clinical manifestations^[2].What's more,RCC has poorer survival than LCC^[3].Given canonical driver mutation genes such as APC,TP53,and KRAS are shared by LCC and RCC,it is tempting to believe that activation of specific oncogenes and/or silencing of tumor suppressors may better explain their prognostic difference and provide clues for treatment as well.Patients with right-sided colon cancer?RCC?generally have a poor prognosis than left-sided colon cancer?LCC?.We previously found that homeobox C6?HOXC6?was the most significantly upregulated gene in RCC compared to LCC.HOXC6,known as a member of homeobox family,not only participates in vertebrate embryonic development^[5],but also was upregulated and played vital roles in various cancer types,such as breast cancer^[7],lung cancer^[8],prostate cancer^[9],and leukemia^[10].In addition to surgery,radiation therapy,chemotherapy and targeted therapy for colorectal cancer,immunotherapy has entered the field of CRC.Since Hopkins'study found that d MMR can screen for immunotherapy advantage populations at 2015,immunotherapy for CRC has begun the MSI era.The components of the immune microenvironment are complex,although studies have shown that M2 tumor-associated macrophages?TAM?^[11],helper T cells^[12]and tumor-associated fibroblasts^[13]alleffect of killing tumors,but the understanding of tumor microenvironment remains to be further studied,which is very important to reveal the causes of tumor immune escape and develop new immunotherapy targets.The interaction between tumor cells and immune cells that surround them is currently poorly understood.Our study aimed to explore the potential oncogenic role,the detailed molecular mechanism and whether participating in regulating TME of HOXC6 in RCC.MethodsExpression datasets from the Cancer Genome Atlas?TCGA?and Gene Expression Omnibus?GEO?database were used to uncover the underlying oncogenic role of HOXC6 in RCC.CCK8,transwell,and tail vein tumor cell injection assays were used to evaluate proliferation,migration,and invasion ability of tumor cells in vitro and vivo.Immunohistochemistry and immunofluorescence were performed to evaluate the correlation of HOXC6 and M2 macrophage infiltration.Western blot,q PCR,ELISA,Co-IP and luciferase reporter assay were performed to examine the association of HOXC6 contributing to epithelial-mesenchymal transition?EMT?.ResultsHOXC6 was overexpressed in RCC and associated with poor prognosis.Elevation of CCL2 expression by upregulation of HOXC6 could attract infiltrating more M2macrophages.IL6 secreted from M2 macrophage could induce EMT of tumor cells by upregulating HOXC6 and activate Wnt/?-catenin signaling pathway via inhibition of DKK1 excretion.Overexpression of HOXC6 promotes migration and invasion of CRC cells in vitro and in vivo.ConclusionOur study indicates that HOXC6 plays an oncogenic role in RCC.Positive crosstalk between M2 macrophages and HOXC6 in tumor cells led to metastasis and poor prognosis of RCC.