Hispidulin prevents hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells
Authors: Jianjun Peng
Jing Xie
Hui Gao
Xuehong Chen
Chunbo Wang
Qixiao Jiang
Yantao Han
Journal: American journal of cancer research (2015)
Discipline: CLINICAL MEDICINE
Keywords: EMT; Hispidulin; Hypoxia; PI3K/Akt; PTEN.
Affiliations: Medical College, Qingdao University Qingdao, Shandong, 266071, China., College of Life Sciences, Chongqing Normal University Chongqing, 401331, China.

Abstract:  Epithelial-mesenchymal transition (EMT) is considered as the most important mechanism that underlies the initiation of cancer metastasis. Here we report that the naturally existing flavonoid, hispidulin is capable of preventing human colorectal cancer cells from hypoxia-induced EMT. The treatment of the cells with hispidulin reversed the EMT-related phenotype that has the morphological changes, down-regulation of E-cadherin, and hypoxia-induced cell migration and invasion. The effect was mediated at least in part by inhibiting the mRNA and protein expressions of HIF-1α via modulation of PTEN/PI3K/Akt pathway. In addition, we found that hispidulin-mediated prevention of the E-cadherin down-regulation and cell motility involved blockade of the hypoxia-induced up-regulation of Snail, Slug and Twist. Hispidulin was also effective in increasing expression of E-cadherin mRNA in HT29 colorectal cancer xenografts implanted in the nude mice. In summary, this study showed that hispidulin can prevent EMT induced by hypoxia, the environment that commonly exists in the center of a solid tumor. Given the low toxicity of hispidulin to the healthy tissues, our study suggests that hispidulin can serve as a safe therapeutic agent for suppressing cancer metastasis. 

Retracted: No

PubPeer comments:
 At right here, Fig 6D .  Western blot analysis to show the effect of hispidulin on:... E-cadherin expression in response to hispidulin, IGF-1 and LY294002. ... D. HT-29 cells were grown under hypoxia in the presence or absence of LY294002 then treatment with IGF-I (10 ng ml) for 2 hours. At left, Fig 3F from [Ding et al (2016)] . ![file] Perhaps the authors of the earlier paper are better-placed to describe exactly how the cells were treated, and what proteins were studied. , 
 #3 Below: Fig 3B:  Hispidulin prevents hypoxia-induced EMT. HT-29 cells growing in hypoxia were treated with hispidulin (25 u03bcM) for 24 hours. ... B. The effect of hispidulin on the expression of E-cadherin examined by florescence staining . Above: Fig 2A from[ Ding et al (2016)] .  PG prevents hypoxia-induced EMT. HCT116 cells are treated for PGat indicated concentration for 24 hours in hypoxia before assays are performed. (A) The representative graphs of the u03b2-catenin translocation determined by immno fluorescent staining were displayed. ![file] Could the authors comment on the similarity of two panels (after 180 deg rotation), despite different descriptions? , 
 why should the authors comment? , 
 Figures have been shown repeatedly in different papers, sometimes with different authors, identified as different cell-lines under different conditions. This invites some kind of explanation. , 
 More versions of the same cells. Upper left, Fig 2 from [Chen et al (2017)] ; lower left, Fig 2 from [Ding et al (2016)] . A right, Fig 3A from [Gao et al (2016) . ![] Identified differently in each appearance. , 
 #1 Extended version - now including Fig 4B from [Han et al (2016)] at right.  Involvement of SOX2 in the modulatory effect of physcion on EMT. SW620 cells were incubated with 5 u03bcmol L physcion for 24 h....(B) Silencing SOX2 suppressed EMT, and the suppressive effects of physcion on EMT was significantly abrogated in SOX2-overexpressing SW620 cells.  ![file] , 
 Above:  Figure 2. Hispidulin suppresses hypoxia-induced migration (A) and invasion (B) in HT-29 cells.  Below, Fig 2B of [Gao et al (2016)] :  Increase PTTG expression enhances MCF-7 cell migration and invasion in vitro. ... B. Cell invasion after transfection was determined by Transwell assay . ![file] Both papers have been cited elsewhere, so I figure that it is worth pointing out the duplicated images. , 
 Fig 7D:  Tumors representing each of the experimental groups . ![file] The high-dose hispidulin panel later became the  Physcion + ADM panel of Fig 6B in [Liu et al (2016)] , illustrating how  Combination of physcion and ADM shows more significant inhibiting effect on tumor growth.  ![] Then further adventures after that: https: pubpeer.com publications BBF2B4BFFF6AE1092929818EEDF14D#3 , 
 Corrected [April 1 2020] . Retracted [1 June 2020] .  A large portion of the data and the text in this article was copied from another source as disclosed by a knowledgeable informant and subsequently confirmed by the Editorial Office. Therefore, the entire article has been retracted in accordance with this journalu2019s policy and Editorial decision. ,