Kawamata Futoshi, Nishihara Hiroshi, Homma Shigenori, Kato Yasutaka, Tsuda Masumi, Konishi Yuji, Wang Lei, Kohsaka Shinji, Liu Cheng, Yoshida Tadashi, Tanino Mishie, Tanaka Shinya, Kawamura Hideki, Kamiyama Toshiya, Taketomi Akinobu
Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Am J Pathol. 2018 Jan;188(1):204-215. doi: 10.1016/j.ajpath.2017.08.034. Epub 2017 Oct 14.
Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment.
游离β人绒毛膜促性腺激素（hCGβ）的异位产生与非滋养层肿瘤的侵袭性行为有关。hCGβ与转化生长因子-β（TGF-β）具有共同的进化序列，而TGF-β是上皮-间质转化（EMT）的主要驱动力。在本研究中，我们研究了hCGβ在EMT过程中的生物学作用及其在结直肠癌（CRC）进展中的临床意义。分析了80份CRC标本和54份术前血清样本。检测了hCGβ过表达的人CRC细胞系的侵袭性和致瘤性，并研究了EMT相关基因的表达。在人类CRC中，组织学hCGβ阳性率[13/80（16.3%）]低于血清学hCGβ阳性率[13/54（24.1%）]。然而，它与几种临床病理特征和不良预后显著相关（P<0.05）。hCGβ过表达的细胞系在小鼠中的侵袭性、迁移能力和转移潜能增加（P<0.01）。蛋白质印迹、PCR和微阵列分析显示，hCGβ改变了EMT相关基因的表达，包括E-钙黏蛋白、磷酸化SMAD2、SNAIL和TWIST。I型和II型TGF-β受体抑制剂可使hCGβ诱导的SNAIL和TWIST过表达水平恢复正常（P<0.05）。因此hCGβ通过TGF-β信号通路诱导EMT，它可能是CRC治疗中的一个分子靶点。
