Cheng Michelle, Ho Samantha, Yoo Jun Hwan, Tran Deanna Hoang-Yen, Bakirtzi Kyriaki, Su Bowei, Tran Diana Hoang-Ngoc, Kubota Yuzu, Ichikawa Ryan, Koon Hon Wai
Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA ; Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Republic of Korea.
Clin Exp Gastroenterol. 2014 Dec 17;8:13-29. doi: 10.2147/CEG.S70906. eCollection 2015.
Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors.
We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial-mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation.
Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation.
Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation.
抗菌肽（人类中的LL-37和小鼠中的mCRAMP）代表一类内源性抗菌和抗炎肽。癌症相关成纤维细胞可促进结肠癌细胞增殖和结肠癌肿瘤生长。
我们利用裸鼠皮下人HT-29结肠癌细胞衍生的肿瘤模型以及C57BL/6小鼠中由氧化偶氮甲烷和葡聚糖硫酸钠介导的结肠癌模型，研究了抗菌肽在结肠癌发生发展中的作用。我们还通过抑制结肠癌细胞的上皮-间质转化（EMT）和成纤维细胞支持的结肠癌细胞增殖来确定抗菌肽的间接抗肿瘤机制。
静脉注射表达抗菌肽的腺相关病毒可显著减小裸鼠HT-29衍生皮下肿瘤的大小、肿瘤衍生胶原蛋白表达和肿瘤衍生成纤维细胞表达。给小鼠抗菌肽肽灌肠可显著减小氧化偶氮甲烷和葡聚糖硫酸钠处理小鼠的结肠肿瘤大小和数量，且不诱导肿瘤及相邻正常结肠组织凋亡。抗菌肽抑制结肠肿瘤中的胶原蛋白表达和波形蛋白阳性成纤维细胞表达。抗菌肽不直接影响HT-29细胞活力，但可显著减少肿瘤生长因子-β1诱导的结肠癌细胞EMT。人结肠CCD-18Co成纤维细胞条件培养基可促进人结肠癌HT-29细胞增殖。抗菌肽预处理可抑制人结肠CCD-18Co成纤维细胞条件培养基介导的结肠癌细胞增殖。抗菌肽破坏结肠成纤维细胞中的微管分布。成纤维细胞中微管的破坏减少了成纤维细胞支持的结肠癌细胞增殖。
抗菌肽通过干扰EMT和成纤维细胞支持的结肠癌细胞增殖有效抑制结肠癌发展。
