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Abstract
Oxytocin (OXT) and its receptor (OXTR) are present in the gastrointestinal system and are involved in gastrointestinal tumorigenesis. However, the effect of OXTR signaling on the development of colorectal cancer (CRC) and its underlying mechanisms remain unexplored. To address these issues, we first examined the expressions of OXT, OXTR, and several cancer-associated proteins using colon “tissue chips” from a spectrum of malignant progression of the colon, which included normal colon tissue, chronic colitis, colorectal adenoma, and colorectal adenocarcinoma (CAC). The results showed that the expressions of OXT and OXTR decreased gradually with the malignant progression of the disease. Stimulation of CAC tissues with OXT increased OXTR expression while down-regulated FAPα and CCL-2 protein expressions in a concentration- and time-dependent manner. Moreover, cell invasion experiment showed that OXT treatment reduced the invasion ability of colon cancer cells and blocking OXTR with atosiban blocked OXT-reduced invasion ability of human colon cancer cell lines Ls174T and SW480. The results indicate that OXT has the potential to inhibit CRC development via down-regulating the immunosuppressive proteins FAPα and CCL-2. When the OXTR signaling is weakened, colon tissues may transform to CRC. These findings also highlight the possibility of applying OXT to inhibit CRC development directly.
Highlights
Colorectal cancer (CRC), a cancer that affects the colon, rectum, or appendix, is the third most common malignant disease in the world and the second most common cancer type in the United States (El-Shami et al, 2015), Europe, and Poland (Witold et al, 2018) in addition to being a leading cause of cancer-related mortality
To reveal the regulation of OXT receptor (OXTR) signaling in the development of colorectal cancer (CRC), expressions of OXT, OXTR, FAPα, and C motif chemokine ligand 2 (CCL-2) were first examined in colorectal adenocarcinoma (CAC) chips
The results showed that the expressions of OXT and OXTR were relatively high in normal tissue, and the expressions in chronic colitis, tubular adenoma, and welldifferentiated CAC decreased gradually (Figure 1)
Summary
Colorectal cancer (CRC), a cancer that affects the colon, rectum, or appendix, is the third most common malignant disease in the world and the second most common cancer type in the United States (El-Shami et al, 2015), Europe, and Poland (Witold et al, 2018) in addition to being a leading cause of cancer-related mortality. With the exception of the United States, the incidence of CRC in most regions of the world is expected to increase continuously in the coming decades, due to population growth and changes in the demographic structure (Tsoi et al, 2017). It has been reported that in all CRC samples examined, FAPα was expressed in cancer-associated fibroblasts, but not in normal colon, hyperplastic polyps, or adenoma samples. CRC cells, but not adenoma cells, can activate fibroblasts by inducing FAPα expression in order to increase their migration and invasion by releasing the transforming growth factor (TGF; Hawinkels et al, 2014). In mouse CRC model, cancer-associated fibroblasts with high FAPα expression induce resistance to immune checkpoint blockade by upregulating C–C motif chemokine ligand 2 (CCL-2) secretion, recruiting myeloid cells, and decreasing T-cell activity (Chen et al, 2017). Clarifying the regulation of FAPα expression in cancer-associated fibroblasts and its associated cytokines probably provide an optional target for suppressing CRC migration
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