Progranulin promoted the proliferation, metastasis, and suppressed apoptosis via JAK2-STAT3/4 signaling pathway in papillary thyroid carcinoma

Background: Progranulin (PGRN), a glycoprotein secreted by a wide range of epithelial cells and plays an important role in inflammatory mechanisms and tumor progression. In this study, the expression, and functions of PGRN in papillary thyroid carcinoma (PTC) was examined to explore the potential pathogenesis of PTC.

Methods: Western blotting and qRT-PCR were used to detect the relationship between PGRN expression and clinicopathological characteristics of patients with PTC. PTC cell lines with PGRN overexpression and with PGRN knockdown were established to explore their effects on the biological behavior. Western blotting was used to detect the changes of relevant molecules and JAK2-STAT3/4 signaling pathway. Moreover, rescue experiments validated the involvement of the JAK2-STAT3/4 signaling pathway. And statistical analyses were analyzed using SPASS 21.0 and graph generation were performed using GraphPad Prism 8.0.

Results: PGRN was overexpressed in PTC tissue and increased by 75% at mRNA level and 161% at relative protein level in the patients with lymph node metastasis compared to without lymph node metastasis. Besides, PGRN regulated and promoted PTC cell proliferation, migration, invasion, and inhibited cell Apoptosis. With PGRN overexpressed, relevant molecules including the expression of BCL2/Bax, BCL2/BAD, CyclinD1, MMP2, vimentin and N-Cadherin were increased, the expression level of E-cadherin was decreased, and the phosphorylation of JAK2 and STAT3/4 were increased. JAK Inhibitor (JSI-124) rescued these changes of PTC cells induced by overexpressed PGRN.

Conclusions: These findings revealed that PGRN promote the progression of PTC through the JAK2-STAT3/4 pathway, and PGRN could be served as a potential therapeutic target for PTC.

Apoptosis; Invasion; JAK2-STAT3/4 pathway; JSI-124; Progranulin; Thyroid neoplasm.