p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells
Authors: Alice S T Wong
Yuen L Pon
Hong Y Zhou
Hextan Y S Ngan
Annie N Y Cheung
Journal: Cancer research (2008)
Discipline: CLINICAL MEDICINE
Keywords: p70 S6 kinase; epithelial to mesenchymal transition (EMT); ovarian cancer; invasiveness; Snail
Affiliations: School of Biological Sciences, University of Hong Kong, Hong Kong.

Abstract:  p70 S6 kinase (p70(S6K)) is a downstream effector of phosphatidylinositol 3-kinase and is frequently activated in human ovarian cancer. Here we show that p70(S6K) functions in epithelial to mesenchymal transition (EMT) responsible for the acquisition of invasiveness during tumor progression. This tumorigenic activity is associated with the ability of p70(S6K) to repress E-cadherin through the up-regulation of Snail. p70(S6K) activation induced phenotypic changes consistent with EMT in ovarian cancer cells: The cells lost epithelial cell morphology, acquired fibroblast-like properties, and showed reduced intercellular adhesion. Western blot showed that p70(S6K) activation led to decreased expression of the epithelial marker E-cadherin and increased expression of mesenchymal markers N-cadherin and vimentin. Inhibition of p70(S6K) by a specific inhibitor or small interfering RNA reversed the shift of EMT markers. Importantly, p70(S6K) activation also stimulated the expression of Snail, a repressor of E-cadherin and an inducer of EMT, but not other family members such as Slug. This induction of Snail was regulated at multiple levels by increasing transcription, inhibiting protein degradation, and enhancing nuclear localization of Snail. RNA interference-mediated knockdown of Snail suppressed p70(S6K)-induced EMT, confirming that the effect was Snail specific. Furthermore, phospho (active)-p70(S6K) staining correlated with higher tumor grade. We also showed a significant positive correlation between p70(S6K) activation and Snail expression in ovarian cancer tissues. These results indicate that p70(S6K) may play a critical role in tumor progression in ovarian cancer through the induction of EMT. Targeting p70(S6K) may thus be a useful strategy to impede cancer cell invasion and metastasis. 

Retracted: No

PubPeer comments:
 The human data on adipose tissue browning reported in this manuscript seems to have been included in another manuscript published around the same time by the same group . Both papers report studying 20 patients with burn injuries on 48u00b12.9% of the body surface. ![file] Both papers report UCP1 expression in fat samples from burned patients and non-burned controls. Although the Cell Reports paper reports two time-points in burn patients, and the the Shock paper only one time point - this time point in the shock paper corresponds to the second time point from the cell reports paper. ![file] Data from slightly different subgroups of patients appear to be used to report fat UCP1 expression (i.e. data are reported from n=8 non burned controls and n=8 burn patients in the Cell Reports paper, but data from n=7 controls and n=10 burn patients are reported in the Shock paper). Thus, while it appears that these data have been generated from samples taken from the same cohort of patients (n=20), the bar graphs presented are not identical. However, some correlations presented in both manuscripts appear to be completely identical. ![file] I could not see any acknowledgement in the shock paper that much of the patient data present were already published - which may give readers the impression that these two papers represent data from two distinct studies. However, I am not sure this is the case. , 
 Two more papers from this group published around the same time presenting UCP1 expression data from adipose tissue samples collected from burn adults. DOI: 10.1097 SLA.0000000000002097 doi: 10.1097 SLA.0000000000002465 , 
 Abdullahi A responding here ( first author of the Shock paper): The human data in the Cell Reports manuscript was a different patient population than that used in the Shock paper as outlined below from the published versions of both papers. There was a typo in the methods section of the Shock paper, the line referring to the patient population (should have said 27%tbsa burns for the shock paper not 48.2%tbsa). The supplemental demographics table available online with the shock paper more accurately defines the patient population used. **Cell Reports Paper** ![file] **Shock Paper: **link to supplemental data for the shock paper that shows the following table can be found at https: journals.lww.com shockjournal Fulltext 2017 01000 IL_6_Signal_From_the_Bone_Marrow_is_Required_for.5.aspx ![file] , 
 Abdullahi A responding here ( first author of the Shock paper): The UCP-1 expression in the two papers are not the same as outlined earlier in our previous comment the patient populations used in these graphs were different. This is outlined below by the respective mean values provided for each respective paper. Additionally, as the figure legends and methods section of each paper outlined, patient cut off points included in the late timepoint were different, eg. Cell reports used patient cohorts from 10-21 days post burn, while the shock paper included all patients in our RTBC repository that were 10 days post burn. In addition to this point, the main message and rationale behind each of the two respective UCP1 data points of the two papers are different. In the cell reports paper an earlier time point was included because the message of that paper was in regards to if browning occurred early vs late in the burn population. The UCP1 human data set in the shock paper was purely there to confirm that those patients with an increased IL-6 also showed UCP1 expression, to set the stage for the papers focus on the mice data showing bone marrow derived IL-6 in regulating browning. **Figure in Cell Reports Paper:** ![file] **Figure in the Shock Paper:** ![file] The Cell reports paperu2019s findings on browning in burn patients was indeed acknowledge in the shock paper, see introduction paragraph #2 and reference #17. We did not further discuss the findings of that paper in the shock manuscript as it was beyond the scope in what our message was in the shock paper. As outlined in the discussion page of the shock manuscript, our primary objective was to identify the source of IL-6 that regulated post burn browning, hence why the mice data was central in the shock manuscript in helping us to answer this aim. We the authors stand behind the data and findings of both papers and their respective conclusions, which have been further confirmed by others in the field of burn research. ,