Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth
Authors: Guo Zhang
Chun-Fang Wang
Li-Hui Wei
Jian-Liu Wang
Li-Jun Zhao
Wen-Juan Qi
Xiao-Ping Li
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: Type 2 diabetes mellitus; hyperinsulinemia; endometrial carcinoma; insulin receptor isoforms; IR-A
Affiliations: Department of Obstetrics and Gynecology, Peking University People's Hospital, Peking University, Beijing, China.

Abstract:  Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR-B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P&lt;0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway. 

Retracted: Yes

PubPeer comments:
 The following concerns were shared with the journal in October 2015. Figure 2: Some of the bands appear to be visible multiple times, as highlighted here with arrows of the same color. ![file] , 
 Figure 6 and Figure 7 appear to look identical. The legend of Figure 7 suggests that something else should have been visible here. ![file] This issue was already reported in 2013 by a user named  BryanHsia - making one wonder if the journal actually cares about readers comments. ![file] , 
 Retracted, [23 November 2021] . ---------------------- Following the publication of this article [1], concerns were raised regarding results presented in Figs 2, 6, and 7. Specifically, The following results appear more similar than would be expected from independent samples: - Fig 2A, IR-B IR-A panel lanes T10 and T15. - Fig 2A, IR-B IR-A panel lanes T11 and T16, and T18. - Fig 2A, IR-B IR-A panel lanes T17 and T19. - Fig 2A, GAPDH panel lanes T10-T11 and lanes T12-T13 respectively. - Fig 2A, GAPDH panel lanes T14-T16 and lanes T17-T19 respectively. - Fig 2B, IR-B IR-A panel lanes N16 and N17. - Fig 2B, GAPDH panel lanes N10-N14 and lanes N15-N19 respectively. The IR-B IR-A panel of Fig 2B appears to have been spliced between N10-N11, N12-N13, N13-N14, and N14-N15. The corresponding GAPDH blot does not appear to have been spliced in the same regions. Fig 6 and Fig 7 report the same results. The submission files indicated that this was likely due to a production error. The authors noted that Fig 6 was published correctly and that the wrong image was published as Fig 7. The authors clarify that the blots presented in Fig 2 were cut and spliced for the purpose of figure beautification. The original data underlying the published results are no longer available. Following discussion of these concerns, the corresponding author requested withdrawal of the article. In light of the unresolved concerns about Fig 2, the PLOS ONE Editors retract this article. All authors agreed with the retraction. CFW, GZ, LJZ, WJQ, and LHW also stated that they stand by the articleu2019s findings and apologize for the issues with the published article. ,