2. Academic Validation
  3. Clonorchis sinensis granulin promotes malignant transformation of human intrahepatic biliary epithelial cells through interaction with M2 macrophages via regulation of STAT3 phosphorylation and the MEK/ERK pathway

Clonorchis sinensis granulin promotes malignant transformation of human intrahepatic biliary epithelial cells through interaction with M2 macrophages via regulation of STAT3 phosphorylation and the MEK/ERK pathway

  • Parasit Vectors. 2023 Apr 24;16(1):139. doi: 10.1186/s13071-023-05765-6.
Qing He # 1 2 3 4,  Xiaowen Pan # 1 2 3 4,  Yingxuan Yin 1 2 3 4,  Anyuan Xu 1 2 3 4,  Xueqing Yi 5,  Yinjuan Wu 6 7 8 9,  Xuerong Li 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
  • 2 Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
  • 3 Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China.
  • 4 China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China.
  • 5 Department of Basic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
  • 6 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China. wuyinjuan@mail.sysu.edu.cn.
  • 7 Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China. wuyinjuan@mail.sysu.edu.cn.
  • 8 Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China. wuyinjuan@mail.sysu.edu.cn.
  • 9 China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China. wuyinjuan@mail.sysu.edu.cn.
  • 10 Department of Parasitology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China. xuerong2@mail.sysu.edu.cn.
  • 11 Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, People's Republic of China. xuerong2@mail.sysu.edu.cn.
  • 12 Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, 510080, People's Republic of China. xuerong2@mail.sysu.edu.cn.
  • 13 China Atomic Energy Authority Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, 100048, People's Republic of China. xuerong2@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 37095578 DOI: 10.1186/s13071-023-05765-6
Abstract

Background: Clonorchis sinensis granulin (CsGRN), a component of the excretory/secretory products of this species, is a multifunctional growth factor that can promote the metastasis of cholangiocarcinoma cells. However, the effect of CsGRN on human intrahepatic biliary epithelial cells (HIBECs) is unclear. Here, we investigated the effect of CsGRN on the malignant transformation of HIBECs and its possible underlying mechanism.

Methods: The malignant transformation phenotypes of HIBECs after CsGRN treatment were estimated by EdU-488 incorporation assay, colony formation assay, wound-healing assay, Transwell assay and western blot. The biliary damage of CsGRN-treated mice was detected by western blot, immunohistochemical staining and hematoxylin and eosin staining. The phenotypes of the macrophages [human monocytic leukemia cell line (THP-1)] were analyzed by flow cytometry, immunofluorescence and immunohistochemistry, both in vitro and in vivo. A co-culture system was developed to explore the interaction between THP-1 and HIBECs in CsGRN-containing medium. Enzyme-linked immunosorbent assay and western blot were used to detected the activation of interleukin 6 (IL-6), phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. An inhibitor of the MEK/ERK pathway, PD98059, was used to determine whether this pathway is involved in CsGRN-mediated cell interactions as well as in STAT3 phosphorylation and malignant transformation of HIBECs.

Results: Excessive hyperplasia and abnormal proliferation of HIBECs, enhanced secretion of hepatic pro-inflammatory cytokines and chemokines, as well as biliary damage, were observed in vitro and in vivo after treatment with CsGRN. The expression of the markers of M2 macrophages significantly increased in CsGRN-treated THP-1 cells and biliary duct tissues compared with the controls. Moreover, following treatment with CsGRN, the HIBECs underwent malignant transformation in the THP-1-HIBECs co-culture group. In addition, high expression of IL-6 was observed in the CsGRN-treated co-culture media, which activated the phosphorylation of STAT3, JAK2, MEK and ERK. However, treatment with an inhibitor of the MEK/ERK pathway, PD98059, decreased expression of p-STAT3 in CsGRN-treated HIBECs and further repressed the malignant transformation of HIBECs.

Conclusions: Our results demonstrated that, by inducing the M2-type polarization of macrophages and activating the IL-6/JAK2/STAT3 and MEK/ERK pathways in HIBECs, CsGRN promoted the malignant transformation of the latter.

Keywords

Clonorchis sinensis granulin; M2 macrophages; MEK/ERK signaling pathway; Malignant transformation; STAT3 phosphorylation.

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