Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer
Authors: Xuehong Chen
Kaili Liu
Mingquan Gao
Mei Han
Hui Gao
Qiaoyun Wang
Bin Zhang
Zhiwu Han
Longyuan Wang
Journal: Cancer science (2018)
Discipline: CLINICAL MEDICINE
Keywords: PIM1; ROS; STAT3; colorectal cancer; hispidulin.
Affiliations: Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China., Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China., Medical College, Qingdao University, Qingdao, China.

Abstract:  Colorectal cancer (CRC) accounts for over 600 000 deaths annually worldwide. The current study aims to evaluate the value of proto-oncogene PIM1 as a therapeutic target in CRC and investigate the anticancer activity of hispidulin, a naturally occurring phenolic flavonoid compound, against CRC. Immunohistochemistry analysis showed that PIM1 was upregulated in CRC tissue. The role of PIM1 as an oncogene was evidenced by the fact that PIM1 knockdown inhibits cell growth, induces apoptosis, and suppresses invasion. Our results showed that hispidulin exerts antitumor activity in CRC through inhibiting the expression of PIM1. Moreover, our findings revealed that hispidulin downregulated the expression of PIM1 by inhibiting JAK2/STAT3 signaling by generating reactive oxygen species. Furthermore, our in vivo studies showed that hispidulin can significantly inhibit tumor growth and metastasis in CRC. Collectively, our results provide an experimental basis for trialing hispidulin in CRC treatment. PIM1 can be considered a potential therapeutic target in CRC. 

Retracted: Yes

PubPeer comments:
 Similar patterns in FACS blots across papers: ![file] ![file] , 
 #1 Another sighting! Fig 1E of [Zou et al (2019)] : ![] , 
 Fig 8,  In vivo efficacy of hispidulin in colorectal cancer tumor growth and metastasis. ... C, Repression in expression of provirus integration site for Moloney murine leukemia virus (PIM1), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and p-JAK2 by hispidulin in tumor tissue  . Tissue samples also appear in 7E from [Niu et al (2019)] [right] **AND** in 6C from [Zou et al (2018)] *[bottom]*. Differently identified. No authors in common. ![] , 
 Here are galleries of histology slices from **six** papers, with **six** non-overlapping teams of nominal authors, sharing surprisingly many slices in common. Identication of each slice in terms of treatment and immunohistochemistry stain is arbitrary. Focussing on connections to the uppermost image, due to lack of colors to show other inter-relationships. Clockwise from top: Fig 7F from [Pan et al (2018)] . Physcion and hepatoceullar carcinoma. 7E from [Niu et al (2019)] . Physcion 8-O-u03b2-glucopyranoside and gastric cancer. Fig 6D from [Wang et al (2018)] . Physcion 8-O-u03b2-glucopyranoside and clear-cell renal cell carcinoma. 6C from [Zou et al (2018)] . Euxanthone and epithelial ovarian cancer. 8C from [Liu et al (2018)] . Hispidulin and colorectal cancer. 8D from [Dou et al (2019)] . Physcion 8-O-u03b2-Glucopyranoside and Testicular Germ Cell Tumors. ![] , 
 *[Above right]* 8C. *[Above left]* Fig 5B,  PG suppresses the expression of Ki-67 and PIM1 while increases the level of cleaved caspase-3 in vivo . from [Wang et al (2017)] . *[Below]* 8D from [Dou et al (2019)] . Other appearances of the panels in this oeuvre could be adduced - identified as different tumors, immunohistochemistry stains, and treatments, and signed by different nominal authors - but there is no need to belabor the point. ![file] , 
 *[Below]*  FIGURE 8 In vivo efficacy of **hispidulin** in **colorectal** cancer tumor growth and metastasis. ... B, Reduction in tumor weight by hispidulin treatment . *[Above]*  Fig. 7. **PG** suppresses growth and metastasis of **gastric** cancer. A: The tumor size was obtained from nude mice . From [Niu et al (2019)] ,  Physcion 8-O-u03b2-glucopyranoside induced ferroptosis via regulating miR-103a-3p GLS2 axis in gastric cancer . ![file] Who would have thought that gastric and colorectal xenograft cancers would appear so similar? , 
 #6 Hat-tip to [Xylocampa Areola] : ![] , 
 (Below) HT29 Control image from Fig 3E is also (above) A549 Control in Fig 2(e), [Zhang et al (2020)] . ![] , 
 #8 Fig 3E is also the source of Fig 6E in [Niu et al (2019)] . ![file] , 
 (Below) Fig 3E and 4D. (Above) Fig 3C from [Yang et al (2019)] :  Autophagy inhibition abrogated the effect of XAG on HCC cell migration and invasion. ... C, Transwell migration (left) and invasion (right) assays of Hep3B and Huh7 cells transfected with Beclinu20101 shRNA or scrambled shRNA, followed by XAG treatment . ![file] Panels are shared. These are different cell-lines and different treatments. Could the authors comment? , 
 Below right: Fig 3E. Above: 3(c) from Yang et al. Now adding 2B from [Fang et al (2010)] to the mix, at lower left. ![] , 
 2020 retraction. https: onlinelibrary.wiley.com doi full 10.1111 cas.14487 The above article from Cancer Science , first published on 25 March 2018 in Wiley Online Library (wileyonlinelibrary.com) and in Volume 109, pp. 1369u20101381, has been retracted by agreement between the authors, the journal Editor in Chief Kohei Miyazono, and John Wiley Sons Ltd. The retraction has been agreed due to the result of Transwell assay displayed in Figures 3E and 4D. They were generated for another study, which has been published as Cell Biochem Funct. 2019 Apr;37(3):128u2010138. ,