Yin Hang, Pan Yue, Li Zhuang, Liu Yong, Chen Jiatong, Chen Xin, Zhang Chengfei, Zhu Feng, Yu Chunzhao
Nanjing Medical University, Nanjing, China.
Department of General Surgery, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, China.
Cancer Med. 2025 Aug;14(15):e71126. doi: 10.1002/cam4.71126.
Collagen triple helix repeat containing 1 (CTHRC1) is a secreted protein involved in tissue remodeling and fibrotic processes, which also suggests emerging roles in cancer. Studies have shown that it is mainly expressed in the outer membrane fibroblasts of injured arteries and in the neointimal smooth muscle cells, where it promotes cell migration and tissue damage repair. However, the regulatory role of CTHRC1 as a tumor microenvironment factor in pancreatic cancer is not well understood.
We employed multi-omics analysis combined with cellular and animal experiments to examine the association between CTHRC1 and the LIF/STAT3 pathway in pancreatic cancer clinical specimens. Using AsPC-1/PANC-1 and other cell lines, we conducted proliferation, migration, invasion, and signaling pathway studies, and elucidated the regulatory mechanism of CTHRC1 through genetic interventions and STAT3 inhibitors.
In this study, we found that CTHRC1 is highly expressed in the cancer-associated fibroblasts (CAFs) of pancreatic cancer and is associated with poor prognosis in patients. Functionally, we observed that CTHRC1 in CAFs promotes the proliferation, migration, and invasion of pancreatic cancer cells both in vitro and in vivo. In mechanistic studies, RNA sequencing revealed that CTHRC1 promotes the proliferation and migration of pancreatic cancer cells through the LIF-mediated STAT3 axis.
These findings reveal the role of CTHRC1 in CAFs in pancreatic cancer, suggesting that it is an attractive therapeutic target and tumor marker. This study uncovers the biological mechanism of CTHRC1 in CAFs in pancreatic cancer, providing new strategies for the treatment of pancreatic cancer.
含胶原蛋白三螺旋重复序列1（CTHRC1）是一种参与组织重塑和纤维化过程的分泌蛋白，这也提示其在癌症中可能发挥新的作用。研究表明，它主要在受损动脉的外膜成纤维细胞和新生内膜平滑肌细胞中表达，在这些细胞中它促进细胞迁移和组织损伤修复。然而，CTHRC1作为胰腺癌肿瘤微环境因子的调节作用尚不清楚。
我们采用多组学分析结合细胞和动物实验，研究胰腺癌临床标本中CTHRC1与LIF/STAT3信号通路之间的关联。利用AsPC-1/PANC-1等细胞系，我们进行了增殖、迁移、侵袭和信号通路研究，并通过基因干预和STAT3抑制剂阐明了CTHRC1的调节机制。
在本研究中，我们发现CTHRC1在胰腺癌的癌症相关成纤维细胞（CAFs）中高表达，且与患者的不良预后相关。在功能上，我们观察到CAFs中的CTHRC1在体外和体内均促进胰腺癌细胞的增殖、迁移和侵袭。在机制研究中，RNA测序显示CTHRC1通过LIF介导的STAT3轴促进胰腺癌细胞的增殖和迁移。
这些发现揭示了CTHRC1在胰腺癌CAFs中的作用，表明它是一个有吸引力的治疗靶点和肿瘤标志物。本研究揭示了CTHRC1在胰腺癌CAFs中的生物学机制，为胰腺癌的治疗提供了新的策略。
