title: Progranulin promotes colorectal cancer proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways.
abstract: Progranulin (PGRN) has been shown to be involved in the process of inflammation, wound healing, and cartilage development; and its role in the progression of breast and ovarian cancer is also well established. However, the expression status of PGRN in colorectal cancers (CRCs) and its molecular mechanisms responsible for tumorigenesis have not been addressed so far. Herein, we demonstrated that PGRN was highly expressed and had clinical relevance with CRCs since its overexpression was associated with advanced stages of CRCs, poorer patients' prognosis, and increased expression of proliferation and angiogenesis markers. PGRN up-regulation significantly promoted the expression of Ki67 and vascular endothelial growth factor A (VEGF-A) as well as the growth rate in CRC cell lines, while PGRN down-regulation had the opposite effects. Strikingly, PGRN derived from CRCs could directly induce proliferation, migration, tubule formation, as well as VEGF-A expression in human umbilical vein endothelial cells (HUVECs). Furthermore, we provided mechanistic evidences that the regulation of Ki67 and VEGF-A expression by PGRN was mediated by tumor necrosis factor receptor 2 (TNFR2)/Akt and the ERK signaling pathways in both CRC cells and HUVECs. Taken together, these findings suggested that PGRN could promote proliferation and angiogenesis through TNFR2/Akt and ERK signaling pathways in CRCs, providing the new insight into the mechanism of PGRN in tumor proliferation and angiogenesis.
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China ; Department of Radiation Oncology, Shandong Cancer Hospital and Institute Jinan 250117, Shandong, P. R. China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University Jinan 250012, Shandong, P. R. China.
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Dong
authors.affiliation: Programs of Cancer Biology, University of Hawaii Cancer Center, University of Hawaii Honolulu 96813, HI, USA.
authors.forename: Yi-Hang
authors.initials: YH
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Medicine School of Shandong University Jinan 250012, Shandong, P. R. China.
authors.forename: Xiao-Sun
authors.initials: XS
authors.lastname: Guo
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Chuan-Yong
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Jinan Central Hospital Affiliated to Shandong University Jinan 250013, Shandong, P. R. China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Sun
keywords: Progranulin (PGRN); angiogenesis; colorectal cancers (CRCs); proliferation; tumor necrosis factor receptor 2 (TNFR2)