Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types that is highly resistant to conventional treatments, such as chemotherapy and radiotherapy. As the demand for more effective therapeutics for PDAC treatment increases, various approaches have been studied to develop novel targets. The cellular communication network (CCN) family is a matricellular protein that modulates various cellular functions, including cell adhesion, proliferation, migration, and invasiveness. Despite this, little is known about the role of CCN6 in PDAC. The current study investigated the role of CCN6 in PDAC by generating CCN6-overexpressing PANC-1 cells (PANC-1-CCN6) by infecting lentivirus particles containing CCN6. PANC-1-CCN6 induces cell viability and tumorigenesis than PANC-1 cells with empty vector (control). The PANC-1-CCN6 formed more colonies, and the size of spheroids increased compared to the control. The upregulation of CCN6 enhances the expression of bone morphogenetic proteins (BMPs) genes and the upregulation of p38 mitogen-activated protein kinases (MAPKs). In PANC-1-CCN6 cells, the levels of N-cadherin, VEGF, and Snail expression were higher than the control, while E-cadherin expression was lower, which is associated with upregulation of epithelial-to-mesenchymal transition (EMT). Consistent with the changes in EMT-related proteins in PANC-1-CCN6, the migratory ability and invasiveness were enhanced in PANC-1-CCN6. Xenografted PANC-1-CCN6 in immunocompromised mice exhibited accelerated tumor growth than the control group. In immunohistochemistry (IHC), the PANC-1-CCN6 xenografted tumor showed an increased positive area of PCNA and Ki-67 than the control. These results suggest that CCN6 plays a tumorigenic role and induces the metastatic potential by the p38 MAPK and BMPs signaling pathways. Although the role of CCN6 has been introduced as an antitumor factor, there was evidence of CCN6 acting to cause tumorigenesis and invasion in PANC-1.
摘要：
胰腺导管腺癌（PDAC）是对常规治疗具有高度抗性的最具侵袭性的癌症类型之一，如化疗和放疗。随着对PDAC治疗更有效疗法的需求增加，已经研究了各种方法来开发新的靶标。细胞通讯网络（CCN）家族是一种调节各种细胞功能的基质细胞蛋白，包括细胞粘附，扩散,迁移,和侵入性。尽管如此,对CCN6在PDAC中的作用知之甚少。目前的研究通过感染含有CCN6的慢病毒颗粒产生CCN6过表达PANC-1细胞(PANC-1-CCN6)来研究CCN6在PDAC中的作用。与具有空载体(对照)的PANC-1细胞相比,PANC-1-CCN6诱导细胞活力和肿瘤发生。PANC-1-CCN6形成了更多的菌落，与对照组相比，球状体的大小增加。CCN6的上调增强骨形态发生蛋白（BMP）基因的表达和p38丝裂原活化蛋白激酶（MAPK）的上调。在PANC-1-CCN6细胞中，N-钙粘蛋白的水平，VEGF,蜗牛的表达高于对照，而E-cadherin表达较低，这与上皮-间质转化（EMT）的上调有关。与PANC-1-CCN6中EMT相关蛋白的变化一致，PANC-1-CCN6中的迁移能力和侵袭力得到增强。免疫受损小鼠中的异种移植PANC-1-CCN6表现出比对照组加速的肿瘤生长。在免疫组织化学（IHC）中，PANC-1-CCN6异种移植肿瘤的PCNA和Ki-67阳性面积比对照组增加.这些结果表明CCN6发挥致瘤作用，并通过p38MAPK和BMPs信号通路诱导转移潜能。虽然CCN6的作用已被引入作为抗肿瘤因子，有证据表明CCN6作用于PANC-1的肿瘤发生和侵袭。
