Liu Yonglei, Yu Conghui, Wu Yonggang, Sun Xiangjun, Su Quanping, You Cuiping, Xin Hongwu
Research Center, Linyi People's Hospital, Shandong, China.
Zhongshan Hospital, Fudan University, Shanghai, China.
J Cell Mol Med. 2017 Sep;21(9):1979-1988. doi: 10.1111/jcmm.13118. Epub 2017 May 18.
CD44, a cell adhesion protein, involves in various process in cancer such as cell survival and metastasis. Most researches on CD44 in cancer focus on cancer cells. Recently, it is found that CD44 expression is high in fibroblasts of tumour microenvironment. However, its role in communication between fibroblasts and breast cancer cells is seldom known. In this study, CD44-positive (CD44 Fbs) and CD44-negative carcinoma-associated fibroblasts (CD44 Fbs) were isolated and cocultured with breast cancer cells for analysis of cell survival and drug resistance. We found that CD44 Fbs promoted breast cancer cell survival and paclitaxel resistance and inhibited paclitaxel-induced apoptosis. Our further research for the molecular mechanism showed that IGF2BP3 bound to CD44 mRNA and enhanced CD44 expression, which increased IGF2 levels of fibroblasts and then stimulated breast cancer cell proliferation and drug resistance. IGF2 was found to activate Hedgehog signal pathway in breast cancer cells. In conclusion, the results illustrated that in CD44 Fbs, binding of IGF2BP3 and CD44 promotes IGF2 expression and then accelerates breast cancer cell proliferation, survival and induced chemotherapy resistance likely by activating Hedgehog signal pathways.
CD44是一种细胞粘附蛋白，参与癌症的多种进程，如细胞存活和转移。大多数关于癌症中CD44的研究都集中在癌细胞上。最近发现，肿瘤微环境中的成纤维细胞中CD44表达较高。然而，其在成纤维细胞与乳腺癌细胞之间通讯中的作用却鲜为人知。在本研究中，分离出CD44阳性（CD44 Fbs）和CD44阴性癌相关成纤维细胞（CD44 Fbs），并与乳腺癌细胞共培养，以分析细胞存活和耐药性。我们发现CD44 Fbs促进乳腺癌细胞存活和对紫杉醇的耐药性，并抑制紫杉醇诱导的细胞凋亡。我们对分子机制的进一步研究表明，IGF2BP3与CD44 mRNA结合并增强CD44表达，这增加了成纤维细胞的IGF2水平，进而刺激乳腺癌细胞增殖和耐药性。发现IGF2可激活乳腺癌细胞中的Hedgehog信号通路。总之，结果表明，在CD44 Fbs中，IGF2BP3与CD44的结合促进IGF2表达，然后可能通过激活Hedgehog信号通路加速乳腺癌细胞增殖、存活并诱导化疗耐药性。
