Low GAS5 expression may predict poor survival and cisplatin resistance in cervical cancer

Yuhan Wang,Tingting Yao,Rongchun Lin,Xingyu Fang,Zhongqiu Lin,Guanglei Zhong

doi:10.1038/s41419-020-2735-2

Yuhan Wang, Tingting Yao + Show 4 more

Open Access

https://doi.org/10.1038/s41419-020-2735-2

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Abstract

Cisplatin resistance is a major challenge in cervical cancer (CC) chemotherapy. Growth arrest‐specific 5 (GAS5) has been reported to be a tumour suppressor gene in CC. However, the mechanism of GAS5 in chemoresistance remains undetermined. Our research evaluated GAS5 expression in normal and CC tissues by qPCR and in situ hybridization (ISH). Statistical analysis was conducted to analyse the association of GAS5 expression with survival. Biochemical methods were used to screen upstream and downstream regulators of GAS5. Then, interactions were confirmed by ChIP, RNA pull-down, RNA immunoprecipitation (RIP), dual-luciferase reporter and real-time PCR assays. The cisplatin sensitivity of GAS5-overexpressing CC cells was demonstrated in vitro and in vivo. The results showed that low GAS5 expression was correlated with poor overall survival. Mechanistically, GAS5 was transcriptionally modulated by P-STAT3 and served as a competing endogenous RNA (ceRNA) of miR-21 to indirectly affect cisplatin sensitivity through PDCD4 regulation in CC cells. Animal studies confirmed that GAS5 enhanced cisplatin sensitivity and promoted PDCD4 expression in vivo. GAS5 was regulated by P-STAT3 and affected the sensitivity of CC to cisplatin-based chemotherapy through the miR-21/PDCD4 axis. This result may provide new insight into cisplatin-based therapy.

Highlights

Cervical cancer (CC) remains the second leading cause of cancer death in women aged 20–39 years
Growth arrest‐specific 5 (GAS5) expression is downregulated in cervical tissues To determine the enrichment of GAS5 in CC, we investigated the expression level of GAS5 in the TCGA database via GEPIA, which indicated a low level of GAS5 in cancer tissues compared to adjacent normal tissues (Fig. 1a)
The quantitative PCR (qPCR) results revealed that GAS5 was expressed at low levels in tumour tissues compared to peritumoral tissues (Fig. 1b)

Summary

Introduction

Cervical cancer (CC) remains the second leading cause of cancer death in women aged 20–39 years. CC mortality among women in less developed countries is twice that of women in affluent countries[1]. Persistent human papillomavirus (HPV) infection, most commonly with HPV16, is a high-risk factor for CC2. Despite advances in surgical resection, chemoradiotherapy and anti-angiogenic therapy for CC, the long-term survival rate of CC patients remains unsatisfactory due to metastasis and recurrence[3,4,5]. Cisplatin (DDP)-based concurrent chemoradiotherapy is the standard treatment for locally advanced CC6. A study found that consolidation chemotherapy after cisplatin-based chemoradiotherapy can control

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