TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion
Authors: Bin Huang
Xin-Gang Li
Chao Zhang
Jian Wang
Xin Zhang
An-Jing Chen
Chao Li
Ran Xu
Journal: Journal of Experimental & Clinical Cancer Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: Autophagy; Galunisertib; Malignant brain tumor; TGF-β; Tumor invasion.
Affiliations: Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Western Rd, Jinan, Shandong, 250012, China., Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan, China., Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Western Rd, Jinan, Shandong, 250012, China. ., Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan, China. ., Department of Biomedicine, University of Bergen, Bergen, Norway. .

Abstract:  Background: Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood. Methods: U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results: Here we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth. Conclusion: Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion. 

Retracted: Yes

PubPeer comments:
 In Figure 1a a micrograph has been duplicated and presented as something else. In Figure 5, a Western immunoblot panel has been duplicated and presented as something else. In Figure 7e, three micrographs have been duplicated and presented as something else. One of them have also been manipulated. ![file] ![file] , 
 #1 An additional finding for Figure 7, marked by blue boxes ![file] , 
 Retracted [20 December 2021] . ----------------- The authors have retracted this article. Concerns were raised regarding a number of figures, specifically; - Figure 1a: the panels for LC3B WHO III and ATG5 WHO IV appear to be identical - Figure 5b: the lanes for Smad and TFG-B2 appear to be identical - Figure 7e: the panels for TGF-B2 LY2157299 and ATG7 LY2157299+CQ appear to be identical - Figure 7e: the panels for ATG5 LY2157299+CQ and MMP9 LY2157299+CQ appear to be identical - Figure 7e: the panels for ATG7 LY2157299 and MMP2 LY2157299+CQ appear to be identical - Figure 7e: the panels for TGF-B2 Con and MMP2 LY2157299 appear to be identical In addition, the authors have stated they found some additional errors in Figs 5c, 5d and 5j. Additionally, the authors have stated they have reviewed the original data and images that should have been included in this article, but given the extent of the misplaced figures, they have agreed to retract the article. The authors would like to apologize for any inconvenience caused by this retraction. All authors agree to this retraction. ,