Tumor endothelial cells promote metastasis and cancer stem cell-like phenotype through elevated Epiregulin in esophageal cancer
Authors: Xiong Shu
Yuliang Ran
Lixin Sun
Long Yu
Lichao Sun
Jian Pan
Huiqi Liu
Zhihua Yang
Jinning Lou
Journal: American journal of cancer research (2016)
Discipline: CLINICAL MEDICINE
Keywords: CD44; EREG; Esophageal cancer; cancer stem cell; metastasis
Affiliations: State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing, People's Republic of China., Department of Hematology and Oncology, Children's Hospital of Soochow University Suzhou, Jiangsu, People's Republic of China., Institute of Clinical Medical Sciences, China-Japan Friendship Hospital Beijing, People's Republic of China.

Abstract:  Tumor endothelial cells have been found to be associated with metastasis and cancer progression. In this study, we reported that human esophageal cancer endothelial cells (HECEC), unlike corresponding human esophageal normal endothelial cells (HENEC) displayed several distinct feature couple with unique gene expression profile. Further studies showed that HECEC can enhance migration, invasion and self-renewal properties of esophageal carcinoma cell in vitro by a direct cell-cell interaction. In vivo assay demonstrated that HECEC could significantly enhance the invasion and lung metastasis of esophageal cancer cells. To elucidate the molecular mechanisms of HECEC in esophageal carcinoma progression, we employed the microarray to analyze the gene expression profiles before and after treating with HECEC, HENEC or conditioned meium from HECEC. Among the highly expressed HECEC-regulated genes, we focused on Epiregulin (EREG). Further studies demonstrated that overexpression of EREG in EC9706 or Kyse30 cells can induce actin reorganization, sphere formation ability and a significantly enrichment of CD44+ cancer stem-like cells. Moreover, up-regulation of EREG in esophageal cancer cells could enhance lung metastasis and decrease the survival time in vivo. Further study indicated that EREG could induce activation of the Src and FAK. In addition, all these effects could also be inhibited by the function-blocking anti-EREG antibody in a dose dependent manner. Immunohistochemical analysis revealed that high level of EREG was significantly correlated with lymph node metastases and poor prognosis. In summary, HECEC play key roles in enhancing the invasion, migration, cancer stem cell phenotype and metastatic potential of esophageal cancer cells through Epiregulin. 

Retracted: No

PubPeer comments:
 *[right]* Fig 7B.  Representative images of tumor xenografts derived from nude mice implanted with agomir-NC- or agomir-605-transfected U251 cells . *[left]* Fig 9A from [Lv, Wang Ma (2019)] .  Representative images of tumor xenografts from nude mice inoculated with Hep3B cells that were transfected with miR-944 mimics or miR-NC . ![file] I have concerns. , 
 #1 The companion paper ([Lv, Wang Ma 2019] ) has been [retracted] . , 
 Retracted [3 September 2021] . --------------------------------- The Editor and Publisher of *OncoTargets and Therapy* wish to retract the published article. Concerns were raised over alleged image duplication in Figure 7B with a similar image from an unrelated study, specifically: - Figure 7B, Agomir-605 appears to have been duplicated with a similar image in Figure 9A, miR-944 mimics from Lv et al, 2019 . The authors responded to our queries but were unable to provide an explanation for the alleged image duplication and could not provide the original raw data for their study and have therefore agreed to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. ,