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Oncogene. 2019 Aug;38(32):6065-6081. doi: 10.1038/s41388-019-0858-7. Epub 2019 Jul 4.

The MRVI1-AS1/ATF3 signaling loop sensitizes nasopharyngeal cancer cells to paclitaxel by regulating the Hippo-TAZ pathway.

Author information

1
Department of Oncology, Third Xiangya Hospital of Central South University, 410013, Changsha, People's Republic of China.
2
Department of Respiration, The Second People's Hospital of Hunan Province of Hunan University of Chinese Medicine, Changsha, 410000, People's Republic of China.
3
Institute of Reproductive and Stem Cell Engineering, Central South University, 410083, Changsha, Hunan, People's Republic of China.
4
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, People's Republic of China.
5
Department of Plastic Surgery, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, People's Republic of China.
6
Department of Gastroenterology, Third Xiangya Hospital of Central South University, 410013, Changsha, People's Republic of China.
7
Cancer Research Institute and Key Laboratory of Carcinogenesis of Ministry of Health, Central South University, 410078, Changsha, People's Republic of China.
8
School of Public Health, Central South University, 410078, Changsha, Hunan, People's Republic of China.
9
Center for Medical Experiments, Third Xiangya Hospital, Central South University, 410013, Changsha, People's Republic of China.
10
Yan'an Affiliated Hospital of Kunming Medical University, 650051, Kunming, People's Republic of China.
11
Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, People's Republic of China.
12
Department of Oncology, Third Xiangya Hospital of Central South University, 410013, Changsha, People's Republic of China. csucaoke@163.com.

Abstract

Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.

PMID:
31273338
DOI:
10.1038/s41388-019-0858-7

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