提高RUNX3表达促进人乳腺癌相关成纤维细胞的肿瘤促进能力。
Increased RUNX3 expression mediates tumor-promoting ability of human breast cancer-associated fibroblasts.
发表日期：2023 Aug 28
作者：
Yu Koyama, Hiroya Okazaki, Yang Shi, Yoshihiro Mezawa, Zixu Wang, Mizuki Sakimoto, Akane Ishizuka, Yasuhiko Ito, Takumi Koyama, Yataro Daigo, Atsushi Takano, Yohei Miyagi, Tomoyuki Yokose, Toshinari Yamashita, Keisuke Sugahara, Okio Hino, Liying Yang, Reo Maruyama, Akira Katakura, Takehiro Yasukawa, Akira Orimo
来源：
Epigenetics & Chromatin
摘要：
乳腺癌相关成纤维细胞（CAFs）是人类乳腺癌的主要基质成分，常常促进肿瘤增殖、进展和恶性程度。我们先前建立了一种实验性CAFs（exp-CAFs）细胞系，具有强大的肿瘤促进能力。通过在小鼠肿瘤移植模型中长时间孵育人类乳腺成纤维细胞系与人类乳腺癌细胞生成。在此研究中，我们发现exp-CAFs高度表达运行相关转录因子3（RUNX3），而对应的成纤维细胞则不表达。乳腺癌患者中，RUNX3阳性的基质成纤维细胞样细胞在癌区的比例较非癌区较高。这些发现提示RUNX3与人类乳腺癌中的CAF特性存在关联。为了研究RUNX3在CAF中的功能作用，分别使用具有或没有RUNX3 shRNA定向敲降的exp-CAFs在免疫缺陷小鼠皮下植入乳腺癌细胞。对比所得到的异种移植瘤发现，在成纤维细胞中抑制RUNX3表达时，肿瘤生长显著减弱。一致的是，肿瘤切片的Ki-67和CD31免疫组织化学染色显示，在抑制RUNX3的exp-CAFs形成的肿瘤中，癌细胞增殖和微血管形成减少。这些结果表明，增加的RUNX3表达可能通过调控癌细胞增长和新生血管生成来促进CAF的肿瘤促进能力。© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Cancer-associated fibroblasts (CAFs) are a major stromal component of human breast cancers and often promote tumor proliferation, progression and malignancy. We previously established an experimental CAF (exp-CAF) cell line equipped with a potent tumor-promoting ability. It was generated through prolonged incubation of immortalized human mammary fibroblasts with human breast cancer cells in a tumor xenograft mouse model.Herein, we found that the exp-CAFs highly express Runt-related transcription factor 3 (RUNX3), while counterpart fibroblasts do not. In breast cancer patients, the proportion of RUNX3-positive stromal fibroblast-like cells tends to be higher in cancerous regions than in non-cancerous regions. These findings suggest an association of RUNX3 with CAF characteristics in human breast cancers. To investigate the functional role of RUNX3 in CAFs, the exp-CAFs with or without shRNA-directed knockdown of RUNX3 were implanted with breast cancer cells subcutaneously in immunodeficient mice. Comparison of the resulting xenograft tumors revealed that tumor growth was significantly attenuated when RUNX3 expression was suppressed in the fibroblasts. Consistently, Ki-67 and CD31 immunohistochemical staining of the tumor sections indicated reduction of cancer cell proliferation and microvessel formation in the tumors formed with the RUNX3-suppressed exp-CAFs.These results suggest that increased RUNX3 expression could contribute to the tumor-promoting ability of CAFs through mediating cancer cell growth and neoangiogenesis in human breast tumors.© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.