Long noncoding RNA LINC00958 regulates cell sensitivity to radiotherapy through RRM2 by binding to microRNA‐5095 in cervical cancer

Abstract

Long noncoding RNAs (lncRNAs) have been implicated in the regulation of resistance to radiotherapy in cervical cancer, which is a type of gynecological disease with high mortality in women around the world. Hence, our purpose is to delineate the involvement of LINC00958 in regulating cell sensitivity to radiotherapy in cervical cancer. LINC00958 expression in cervical cancer was assayed, followed by verification of the relationship among LINC00958, microRNA-5095 (miR-5095) and ribonucleotide reductase subunit M2 (RRM2). Hela cells were transduced with up-/downregulation of miR-5095 or RRM2, or LINC00958 silencing, respectively, and then treated with or without a 6 Gy dose of X-ray irradiation. Then the cell proliferation, apoptosis, survival fraction rate, as well as sensitivity to radiotherapy, were assessed. Finally, xenograft tumor in nude mice was established by transplanting Hela cells transfected with sh-LINC00958 and irradiated with 6 Gy of X-ray. High expression of LINC00958 was revealed in The Cancer Genome Atlas and GeneExpression Profiling Interactive Analysis, as well as in radiation-resistant patients, which was associated with lower sensitivity to radiotherapy in cervical cancer. Moreover, cervical cancer patients with higher LINC00958 expression exhibited a shorter overall survival according to Kaplan-Meier analysis. In addition, LINC00958 could regulate the expression of RRM2 by competing for miR-5095. A combination of radiotherapy with LINC00958 silencing, RRM2 downregulation or miR-5095 overexpression was found to inhibit cervical cancer cell proliferation and tumor growth, while promoting cell apoptosis both in vitro and in vivo. Collectively, our results suggest that LINC00958 could regulate RRM2 by competing to miR-5095, which regulates cell sensitivity to radiotherapy in cervical cancer. K E Y W O R D S cervical cancer, long noncoding RNA LINC00958, microRNA-5095, ribonucleotide reductase subunit M2, sensitivity to radiotherapy 1 | BACKGROUND Cervical cancer, one of the commonest types of gynecological malignancies, presents an increased incidence in the younger population in recent years (Wu et al., 2018). Current treatment approaches for cervical cancer include surgery, radiotherapy and cytotoxic chemotherapy (Lin et al., 2018). However, the 5-year survival rate remains unsatisfactory due to the fact that the majority of the patients with cervical cancer is often diagnosed at an advanced stage with distant and lymph node metastasis occurred (Dong, Wang, Li, & Xiao-Jin, 2018).

SP1 induced long non-coding RNA LINC00958 overexpression facilitate cell proliferation, migration and invasion in lung adenocarcinoma via mediating miR-625-5p/CPSF7 axis

“…The inhibitory effects of LINC00958 knockdown on LAD cells proliferation, migration and invasion revealed the oncogenic properties of LINC00958 in LAD. This observation showed similarity to the reports of enriched present research on the oncogenic nature of LINC00958 in pancreatic cancer, gastric cancer (GC) and cervical cancer [26][27][28].…”

<p>Long Noncoding RNA SNHG7, a Molecular Sponge for microRNA-485, Promotes the Aggressive Behavior of Cervical Cancer by Regulating PAK4</p>

“…Nowadays, a variety of lncRNAs are known to be dysregulated in cervical cancer. [54][55][56] Accumulating evidence has confirmed the contribution of lncRNA dysregulation to the aggressiveness of cervical cancer, although only a few lncRNAs have been validated as being involved in cervical cancer. [57][58][59] Therefore, identifying the lncRNAs associated with cervical cancer will improve our knowledge of the role of lncRNAs in the malignancy of cervical cancer, thus highlighting their usefulness as therapeutic and/or prognostic targets in cervical cancer.…”

<p>Long Noncoding RNA <em>ZFPM2-AS1</em> Enhances the Malignancy of Cervical Cancer by Functioning as a Molecular Sponge of microRNA-511-3p and Consequently Increasing FGFR2 Expression</p>

“…Extensive research has confirmed aberrant expression of lncRNAs in cervical cancer. 21,47,48 The dysregulation of lncRNAs has been demonstrated to be crucial for cervical carcinogenesis and cervical cancer progression through the control of a wide range of aggressive characteristics of cancer cells. [49][50][51] Accordingly, lncRNAs may be promising RNAs for the identification of novel chemotherapeutic medications.…”

“…Functionally, the aberrantly expressed lncRNAs exert cancer-inhibiting or cancer-promoting actions and thereby serve as critical modulators of cervical carcinogenesis by affecting a number of malignant characteristics. [21][22][23] Therefore, an in-depth understanding of the functions of lncRNAs in cervical cancer is crucial for improving the disease diagnosis, prognosis, and treatments.…”