CD44s Induces miR-629-3p Expression in Association with Cisplatin Resistance in Head and Neck Cancer Cells.

Junichiro Chikuda,Masahiro Nagasaki,Kurataka Otsuka,Iwao Shimomura,Yusuke Yamamoto,Hiroaki Miyazaki,Kagenori Ito,Toshikazu Shimane,Yoshiki Mukudai,Tatsuo Shirota,Ryou-U Takahashi,Takahiro Ochiya

doi:10.3390/cancers12040856

Junichiro Chikuda, Masahiro Nagasaki + Show 10 more

Open Access

https://doi.org/10.3390/cancers12040856

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Abstract

Cisplatin (cis-diamminedichloroplatinum II [CDDP] ) is a well-known chemotherapeutic drug that has been used for the treatment of various types of human cancers, including head and neck cancer. Cisplatin exerts anticancer effects by causing DNA damage, replication defects, transcriptional inhibition, cell cycle arrest, and the induction of apoptosis. However, drug resistance is one of the most serious problems with cancer chemotherapy, and it causes expected therapeutic effects to not always be achieved. Here, we analyzed global microRNA (miRNA) expression in CD44 standard form (CD44s)-expressing SAS cells, and we identified miR-629-3p as being responsible for acquiring anticancer drug resistance in head and neck cancer. The introduction of miR-629-3p expression inhibited apoptotic cell death under cisplatin treatment conditions, and it promoted cell migration. Among the computationally predicted target genes of miR-629-3p, we found that a number of gene expressions were suppressed by the transfection with miR-629-3p. Using a xenografting model, we showed that miR-629-3p conferred cisplatin resistance to SAS cells. Clinically, increased miR-629-3p expression tended to be associated with decreased survival in head and neck cancer patients. In conclusion, our data suggest that the increased expression of miR-629-3p provides a mechanism of cisplatin resistance in head and neck cancer and may serve as a therapeutic target to reverse chemotherapy resistance.

Highlights

Oral cancer is a malignant tumor that is categorized as a type of head and neck cancer
According to principal component analysis (PCA) with global miRNA expression, we found that the expression profiles of SAS/CD44 standard form (CD44s) cells were obviously distinct from those of SAS/GFP
We demonstrated that the expression of 14 miRNAs including miR-629-3p was upregulated in SAS/CD44s cells, which are resistant to CDDP; further, enhanced miR-629-3p expression inhibited apoptotic cell death and promoted cellular migration

Summary

Introduction

Oral cancer is a malignant tumor that is categorized as a type of head and neck cancer. In 2018, more than 150,000 individuals died from oral cancer, and more than 350,000 newly developed this type. In Japan, oral cancers are the 10th highest incidence in men and the 14th highest incidence in women [2]. In some cases, cancer cells are resistant to CDDP, and chemotherapy does not respond. It is an obstacle to anticancer drug treatment; anticancer drug resistance is one of the most severe problems of current cancer chemotherapy [5]. Since the oral cavity has a variety of functions, such as feeding, swallowing, and speech, it has a large influence on daily life when poor clinical outcomes occur, especially in recurrent or advanced oral cancer that arise from the development of drug resistance. Cancer stem cells (CSCs) have a high drug resistance and tumorigenic potential and are thought to be closely involved in recurrence and metastasis [6]

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