Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer
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Linlin Wang1,2,*, Dong Yang3,*, Jing Tian4, Aiqin Gao2, Yihang Shen5, Xia Ren6, Xia Li6, Guosheng Jiang6, Taotao Dong7
1Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, Shandong 250117, P. R. China
2Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R.China
3Department of Oncology, Affiliated hospital of Jining Medical College, Jining, Shandong 272129, P. R. China
4Department of Oncology, People's Hospital of Zhangqiu City, Zhangqiu, Shandong 250200, P. R. China
5Programs of Cancer Biology, University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
6Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250012, P. R. China
7Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P. R. China
*These authors contributed equally to the study
Taotao Dong, email: firstname.lastname@example.org
Guosheng Jiang, email: Jiangguosh@163.com
Keywords: PGRN, colorectal cancer, cancer associated fibroblasts, TNFR2, AKT
Received: September 27, 2016 Accepted: February 06, 2017 Published: February 17, 2017
Cancer associated fibroblasts (CAFs) are a crucial cellular component in tumor microenvironment and could promote tumor progression. CAFs are usually derived from resident fibroblasts, which undergoing an activated process stimulated by tumor cells. However, the agents and mechanism driving this switch have not yet been elucidated. Progranulin (PGRN), a well acknowledged secreted glycoprotein, could promote proliferation and angiogenesis of colorectal cancer (CRC) cells, and high expression of PGRN correlated with patient poor prognosis. Whether PGRN has effects on the function of stromal fibroblasts is unknown. Herein we found that there was a positive correlation between PGRN expression of CRC cells and expressions of smooth muscle actin α (α-SMA) on CAFs in CRC patient tissues. PGRN/α-SMA co-expression was positively correlated with CRC patient poor prognosis. Co-cultured with CRC cells or human recombinant PGRN (rPGRN), the expression of Ki67, fibroblast activation protein (FAP) and α-SMA in fibroblasts were all up-regulated significantly, accompanying with elevated cellular proliferation, migration and contraction. Whilst co-cultured with PGRN-silenced CRC cells, these functions were down-regulated. Studies of the underlying molecular mechanism demonstrated that either tumor necrosis factor receptor 2 (TNFR2)/Akt or the extracellular regulated kinase (ERK) signaling pathway contributed to modulate of Ki67, FAP, and α-SMA expression, and correlated to abilities of proliferation, migration and contraction in fibroblasts. In conclusion, PGRN plays an important role in activation of CRC fibroblasts, which may be taken as a prospective target of CRC therapy.
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