CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways.
CCL20 induces colorectal cancer neoplastic epithelial cell proliferation, migration, and further CCL20 production through autocrine HGF-c-Met and MSP-MSPR signaling pathways.
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CCL 20通过自分泌HGF-c-Met和MSP-MSPR信号通路诱导结直肠癌肿瘤上皮细胞增殖、迁移和进一步产生CCL 20。
DOI：
10.18632/oncotarget.28131
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发表时间：
2021-11-23
期刊：
影响因子：
--
通讯作者：
Gold JS
中科院分区：
文献类型：
--
作者：
Nandi B;Del Valle JP;Samur MK;Gibbons AJ;Prabhala RH;Munshi NC;Gold JS
CCL 20-CCR 6相互作用通过直接作用于肿瘤上皮细胞和通过调节肿瘤微环境来促进结直肠癌。这些作用于肿瘤上皮细胞的机制知之甚少。这项研究表明，CCL 20诱导肝细胞生长因子（HGF）的分泌和HGF的同源受体c-Met的磷酸化在HT 29和HCT 116结直肠癌细胞系中的浓度和时间依赖性的方式。与CCL 20类似，HGF诱导结肠癌细胞中的迁移、CCL 20的自反馈分泌和ERK 1/2磷酸化。CCL 20依赖性ERK 1/2磷酸化被HGF抑制阻断，CCL 20依赖性迁移和CCL 20分泌被HGF或ERK抑制阻断。有趣的是，与CCL 20不同，HGF不诱导结肠癌细胞的增殖，并且CCL 20依赖性细胞增殖不被直接HGF抑制所阻断。然而，CCL 20依赖性增殖被多酪氨酸激酶抑制剂克唑替尼阻断。探索这种作用，发现CCL 20还诱导结肠直肠癌细胞产生MSP和MSP的受体MSPR的磷酸化。通过直接阻断MSP-MSPR相互作用来抑制CCL 20依赖性细胞增殖。因此，CCL 20介导的迁移和CCL 20分泌通过涉及HGF、c-Met和ERK的途径调节，而CCL 20介导的增殖则通过MSP及其受体MSPR调节。
CCL20-CCR6 interactions promote colorectal cancer through direct effects on neoplastic epithelial cells and through modulating the tumor microenvironment. The mechanism of these effects on neoplastic epithelial cells is poorly understood. This study demonstrates that CCL20 induces secretion of hepatocyte growth factor (HGF) and phosphorylation of HGF’s cognate receptor c-Met in HT29 and HCT116 colorectal cancer cell lines both in concentration- and time-dependent manners. Similar to CCL20, HGF induces migration, autofeedback CCL20 secretion, and ERK1/2 phosphorylation in the colon cancer cells. CCL20-dependent ERK1/2 phosphorylation is blocked by HGF inhibition, and CCL20-dependent migration and CCL20 secretion are blocked by inhibition of HGF or ERK. Interestingly, unlike CCL20, HGF does not induce proliferation of colon cancer cells, and CCL20-dependent cell proliferation is not blocked by direct HGF inhibition. CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib. Exploring this effect, it was found that CCL20 also induces production of MSP and phosphorylation of MSP’s receptor MSPR by the colorectal cancer cells. CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.