Critical role of SOX2\u2013IGF2 signaling in aggressiveness of bladder cancer

Yu-Fan Chiu,Junn-Liang Chang,Ming-Yi Zheng,Yuan-Hung Wang,Chia-Chang Wu,Pei-Yu Chen,Yu-Ting Chou,Sheng-Chieh Lin,Ming-Han Kuo,Chia-Cheng Miao

doi:10.1038/s41598-020-65006-z

Abstract

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low-serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells’ spheroid-forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated spheroid formation of bladder cancer cells. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished bladder cancer cell growth. Lastly, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Our findings indicate the SOX2–IGF2 signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.

Highlights

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC mediates reprogramming of differentiated cells to pluripotency but has been correlated with tumor malignancy
Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC has been associated with cancer progression in several tumors, it has remained unclear how these signaling molecules mediate bladder cancer progression
We found that SOX2, but not OCT4, KLF4, or MYC expression, correlates with poor prognosis and histologic differentiation in bladder cancer

Summary

Introduction

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC mediates reprogramming of differentiated cells to pluripotency but has been correlated with tumor malignancy. We found SOX2 promotes AKT phosphorylation in bladder cancer cells by inducing IGF2 and IGF1R expression www.nature.com/scientificreports analysis to assess SOX2 mRNA and protein expression, respectively, in T24 cells transduced with the lentiviral vector encoding SOX2 cDNA (SOX2) or empty control vector (Ctrl). Clonogenic analysis showed that SOX2 expression promoted T24 cell growth under a low-serum (1% FBS) condition (Fig. 3a).

Results

Conclusion