Modulating PCGF4 Stability Is an Efficient Metastasis-Regulatory Strategy Used by Distinct Subtypes of Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma

Jinjing Hu; Hao Xu; Xiaojun Ma; Mingzhen Bai; Yongqiang Zhou; Ruidong Miao; Fanghong Wang; Xun Li; Bo Cheng

doi:10.1016/j.ajpath.2024.03.012

Modulating PCGF4 Stability Is an Efficient Metastasis-Regulatory Strategy Used by Distinct Subtypes of Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma

Am J Pathol. 2024 Apr 24:S0002-9440(24)00160-3. doi: 10.1016/j.ajpath.2024.03.012. Online ahead of print.

Authors

Jinjing Hu¹, Hao Xu², Xiaojun Ma³, Mingzhen Bai⁴, Yongqiang Zhou⁴, Ruidong Miao³, Fanghong Wang², Xun Li⁵, Bo Cheng⁶

Affiliations

¹ School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
² The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.
³ School of Life Sciences, Lanzhou University, Lanzhou, China.
⁴ The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.
⁵ The First School of Clinical Medicine, Lanzhou University, Lanzhou, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China. Electronic address: lix@lzu.edu.cn.
⁶ School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou, China. Electronic address: bocheng@lzu.edu.cn.

PMID: 38670529
DOI: 10.1016/j.ajpath.2024.03.012

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a 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 cancer-promoting categories based on distinct tumorigenic effects. The RNA-sequencing analyses of ICC cancerous cell lines identified B-lymphoma Mo-MLV insertion region 1 (PCGF4; alias 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, and stemness properties. Mechanistically, cancer-restraining CAFs triggered the proteasome-dependent degradation of PCGF4, whereas cancer-promoting CAFs enhanced the stability of PCGF4 via activating the IL-6/phosphorylated 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.