Modulating PCGF4 stability is an efficient metastasis-regulatory strategy utilized by distinct subtypes of Cancer-Associated Fibroblasts in intrahepatic cholangiocarcinoma

Intrahepatic Cholangiocarcinoma (ICC) is highly malignant neoplasm and prone to metastasis. It is unclear if cancer-associated fibroblasts (CAFs) affect the metastasis of ICC. Here, we have established ICC patient-derived CAF lines and related cancerous cell lines and analyzed the effects of CAFs on the tumor progressive properties of the ICC cancerous cells. Results demonstrated that CAFs can be classified into cancer-restraining or promoting categories (rCAFs or pCAFs) based on distinct tumorigenic effects. The RNA-Seq analyses of ICC cancerous cell lines identified B lymphoma Mo-MLV insertion region 1 (PCGF4, also known BMI1) as a potential metastasis regulator. Strikingly, the changes of PCGF4 levels in ICC cells perfectly mirrored the restraining or promoting effects of CAFs on ICC migration. Our Immunohistochemical analyses on the ICC tissue microarrays indicated that PCGF4 was negatively correlated to overall survival of ICC. We confirmed the promoting effects of PCGF4 on cell migration, drug resistance activity, stemness properties. Mechanistically, rCAFs triggered the proteasome-dependent degradation of PCGF4, while pCAFs enhanced the stability of PCGF4 via activating the IL-6/p-STAT3 pathway. In summary, our data identified roles of CAFs on ICC metastasis and revealed a new mechanism of the CAFs on ICC progression in which PCGF4 acted as the key effector by both categories of CAFs. These findings shed light on developing comprehensive therapeutic strategies for ICC.