β2AR-HIF-1α-CXCL12 signaling of osteoblasts activated by isoproterenol promotes migration and invasion of prostate cancer cells
Authors: Ruonan Gu
Guihuan Li
Shiyuan Xu
Zhishuai Zhang
Zhong-Kai Cui
Zhibin Huang
Fan Deng
Xiaoju Lai
Fangyin Zeng
Wenyang Wang
Journal: BMC Cancer (2019)
Discipline: CLINICAL MEDICINE
Keywords: Bone metastasis; Cancer; Chronic stress; Sympathetic nerve.
Affiliations: Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China., Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China., Department of Anesthesiology, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, 350001, China., Department of Clinical Laboratory, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900, China. ., Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. ., Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. .

Abstract:  Background: Chronic stress is well known to promote tumor progression, however, little is known whether chronic stress-mediated regulation of osteoblasts contributes to the migration and invasion of metastatic cancer cells. Methods: The proliferation, migration and invasion of prostate cancer cells were assessed by CCK-8 and transwell assay. HIF-1α expression of osteoblasts and epithelial-mesenchymal transition (EMT) markers of prostate cancer cells were examined by Western blot. The mRNA level of cytokines associated with bone metastasis in osteoblasts and EMT markers in PC-3 and DU145 cells were performed by qRT-PCR. Functional rescue experiment of cells were performed by using siRNA, plasmid transfection and inhibitor treatment. Results: Isoproterenol (ISO), a pharmacological surrogate of sympathetic nerve activation induced by chronic stress, exhibited no direct effect on migration and invasion of PC-3 and DU145 prostate cancer cells. Whereas, osteoblasts pretreated with ISO promoted EMT, migration and invasion of PC-3 and DU145 cells, which could be inhibited by β2AR inhibitor. Mechanistically, ISO increased the secretion of CXCL12 via the β2AR-HIF-1α signaling in osteoblasts. Moreover, overexpression of HIF-1α osteoblasts promoted migration and invasion of PC-3 and DU145 cells, which was inhibited by addition of recombinant knockdown of CXCR4 in PC-3 and DU145 cells, and inhibiting CXCL12-CXCR4 signaling with LY2510924 blunted the effects of osteoblasts in response to ISO on EMT and migration as well as invasion of PC-3 and DU145 cells. Conclusions: These findings demonstrated that β2AR-HIF-1α-CXCL12 signaling in osteoblasts facilitates migration and invasion as well as EMT of prostate cancer cells, and may play a potential role in affecting bone metastasis of prostate cancer. 

Retracted: No

PubPeer comments:
 In Figure 2C, microscopy data has been duplicated and presented as something else (Invasion, PCR; last two micrographs). ![file] , 
 #1 We wish to thank you for your insightful comment. We are sorry for the misplacement and inadvertent duplication of the images in Figure 2C, occurring during preparation and insertion of the image in the last two neighboring micrographs in Figure 2C, although the main conclusion of the article is not affected by the flaw. We deeply regret any inconvenience this event has caused for other authors and readers. The correction version of Figure 2 is as follows. We also have sent a correction letter and correction of Figure 2 to BMC Cancer editor on February 8th, 2020. Thank you again for your comments. ![file] ,