Downregulation of HMGA1 Mediates Autophagy and Inhibits Migration and Invasion in Bladder Cancer via miRNA-221/TP53INP1/p-ERK Axis.

Xiaoqiang Liu,Bin Fu,An Xie,Yu Li,Ke Zhu,Luyao Chen,Tao Zeng,Yulei Li,Gongxian Wang,Xiaochen Zhou,Yibing Wang,Zhengtao Zhou,Wen Deng

doi:10.3389/fonc.2020.00589

Abstract

MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.

Highlights

Bladder cancer (BC) is the fourth most common cancer in men in the United States with an estimated 62,380 new cases and 12,520 deaths in 2018 [1]
We showed that miR221 was significantly upregulated or unchanged in invasive BC lines (T24, J82, EJ, UM-UC-3) but downregulated in the noninvasive BC cell line (5637) (Figure 1A), which indicated that the overexpression of miR-221 might be correlated to muscle-invasive BC (MIBC)
Given that our previous study showed that the downregulation of miR-221 inhibits the migration and invasion of BC cells, we investigated whether miR-221 could influence autophagy of BC cells

Summary

Introduction

Bladder cancer (BC) is the fourth most common cancer in men in the United States with an estimated 62,380 new cases and 12,520 deaths in 2018 [1]. 75% of cases are non-muscle-invasive BC (Ta, T1), which has a good prognosis, with 94% of patients surviving ≥5 years and is usually treated by transurethral resection and intravesical chemotherapy [2]. Approximately half of these patients will experience cancer recurrence, and 20% will progress to muscle-invasive BC (MIBC), which requires additional surgical interventions and chemotherapy [3]. Few patients are initially diagnosed with MIBCs, the 5-year survival of patients with MIBC is low: nearly 50.1% for regional stage and 10.2% for distant stage [4]. Despite the crucial advances in BC research this year, the mortality rate of BC has remained unchanged due to the lack of specific targets [5].

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Conclusion