Circular RNA PRKCI silencing represses esophageal cancer progression and elevates cell radiosensitivity through regulating the miR-186-5p/PARP9 axis
Introduction
Esophageal cancer (EC) is a common malignant tumor, its two main pathological types are esophageal adenocarcinoma and esophageal squamous cell carcinoma [1]. Its 5-year survival rate is less than 25% and ranks sixth among cancer death causes [2]. After surgery for EC patients, radiotherapy plays a vital role in controlling local tumors [3]. However, radioresistance often leads to local tumor recurrence and poor prognosis [4]. Hence, exploring the molecular mechanisms of EC radioresistance is indispensable for improving the prognosis of EC patients.
Circular RNAs (circRNAs) are a new class of non-coding RNAs, which are characterized by the formation of a covalently closed circular structure through reverser splicing [5]. CircRNAs have attracted the attention of researchers because of their high stability and their regulatory effect on gene expression [6]. CircRNAs have been demonstrated to be involved in the advancement of a series of cancers [7,8]. Furthermore, circRNAs are associated with the chemoresistance of various cancers [[9], [10], [11]]. Circular RNA protein kinase C iota (circPRKCI) is formed by the reverse splicing of two exons (15 and 16) of the PRKCI gene, and its length is 1484 bp [12]. CircPRKCI was revealed to be related to the development of diverse cancers, such as gastric cancer [13], hepatocellular cancer [14], lung adenocarcinoma [15], and glioma [16]. Also, circPRKCI participated in EC progression [17]. Nevertheless, the role of circPRKCI in EC radioresistance is unclear.
MicroRNAs (miRNAs) are small non-coding RNA molecules that exert an important role in gene translation suppression and silencing by binding to target mRNAs [18]. MiRNAs are involved in a series of cellular processes, such as cell inflammation, differentiation, cycle progression, migration, and apoptosis [19]. MicroRNA-186-5p (miR-186-5p) was reported to be connected with the progression of a variety of cancers [[20], [21], [22]]. Besides, miR-186-5p enhancement could inhibit HOXA9 expression, which repressed cell metastasis and proliferation in EC [23]. However, the function of miR-186-5p in EC redioresistance was rarely reported.
Poly ADP-ribose polymerase (PARP) is a protein family found in prokaryotes and eukaryotes, which contains 18 enzymes that participate in cellular processes [24]. Although PARP9 has a carboxy-terminal amino acid sequence similar to other members of the PARP family, it lacks PARP activity [25]. Previous study indicated that enhanced PARP9 expression could accelerate cell tumorigenicity in cervical cancer [26]. Moreover, PARP9 overexpression promoted cell migration in breast cancer [27]. However, whether PARP9 can be regulated by circPRKCI and miR-186-5p in EC radioresistance is indistinct.
In the current study, we demonstrated that circPRKCI regulated EC advancement and radioresistance through regulating PARP9 expression via sponging miR-186-5p, which provided an evidence for circPRKCI as a target in EC treatment.
Section snippets
EC specimen collection
57 paired EC tissues and adjacent normal tissues were obtained from Second Affiliated Hospital of Xi'an Jiao Tong University. This research was reviewed and approved by the Ethics Committee of Second Affiliated Hospital of Xi'an Jiao Tong University. Patients with EC who participated in this study signed the informed consents.
Cell culture and transfection
Human normal esophageal epithelial cells (THEECs) and EC cells (TE-1, KYSE410, ECA-109, and KYSE450) were obtained from Bena culture collection (Jiangsu, China). The
CircPRKCI and PARP9 expression were increased in EC tissues and cells
To verify the expression pattern of circPRKCI in EC, we assessed the level of circPRKCI in 57 paired EC tissues and adjacent normal tissues. QRT-PCR manifested that circPRKCI expression was signally elevated in EC tissues in comparison to the adjacent normal tissues (Fig. 1A). Consistently, circPRKCI expression was also elevated in EC cells (TE-1, KYSE410, ECA-109, and KYSE450) compared to the THEECs cells (Fig. 1B). Moreover, circPRKCI expression was evidently decreased by using Oligo (dT)18
Discussion
Increasing researches have demonstrated that the abnormal expression of circRNAs is connected with EC radiosensitivity. For example, Liu et al. demonstrated that circRNA_100367 regulated the miR-217/Wnt3 pathway in EC cells, which increased the radioresistance of EC [29]. Another study proved that circRNA VRK1 could constrain EC progression and elevate cell radiosensitivity through the miR-624-3p/PTEN/PI3K/AKT pathway [30]. In this study, we demonstrated that reduced circPRKCI expression could
Declaration of competing interest
The authors declare that they have no financial conflicts of interest.
Acknowledgement
None.
Funding
This work was supported by Key research and development projects of Shaanxi Province (No. 2019SF-221) and National Natural Science Foundation of China (No. 81903268).
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These authors contributed equally to this paper.