Silencing of the lncRNA H19 enhances sensitivity to X-ray and carbon-ions through the miR-130a-3p /WNK3 signaling axis in NSCLC cells

Abstract

Background The lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown. Methods The expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells. Flow cytometry and Western blotting were conducted to measure the level of apoptosis. The binding relationship between the lncRNA H19 and miR-130a-3p was determined by a dual-luciferase reporter assay. A binding relationship was also identified between miR-130a-3p and With-No-Lysine Kinase 3 (WNK3). Results Expression patterns of lncRNAs revealed that the lncRNA H19 was upregulated in radioresistant NSCLC (A549-R11) cells compared with A549 cells. Knockdown of the lncRNA H19 enhanced the sensitivity of NSCLC cell lines to X-ray and carbon ion irradiation. Mechanistically, the lncRNA H19 serves as a sponge of miR-130a-3p, which downregulates WNK3 expression. The lncRNA H19–miR-130a-3p–WNK3 axis modulates radiosensitivity by regulating apoptosis in NSCLC cell lines. Conclusion Knockdown of the lncRNA H19 promotes the sensitivity of NSCLC cells to X-ray and carbon ion irradiation. Hence, the lncRNA H19 might function as a potential therapeutic target that enhances the antitumor effects of radiotherapy in NSCLC.

LncRNA H19 Impairs Chemo and Radiotherapy in Tumorigenesis

“…Temozolomide (TMZ), an oral alkylating drug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas [ 96 ]. TMZ treatment ( Figure 3 ) blocks the cell cycle at G2/M stage, leading to maligned cells towards cellular apoptosis [ 97 ].…”

Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer

“…Liu et al found that circRNA ZNF208 significantly enhanced the resistance of NSCLC cells to X-rays, but the sensitivity to carbon ions did not change [29]. In addition to circRNA ZNF208, the down-regulation of lncRNA H19 also increases the sensitivity of NSCLC cells to heavy ions [30]. Therefore, these ncRNAs might function as a potential therapeutic target to enhance the efficacy of heavy ion radiotherapy for NSCLC.…”

An update regarding the role of WNK kinases in cancer

“…MicroRNAs (miRNAs) are small ncRNAs that post-transcriptionally repress gene expression via binding to the 3′-untranslated region of target mRNAs [ 116 ]. MiR-93, miR-130a, miR-210a, miR-524a, and miR-620 are found to directly target oncogenic WNK1/3 or antitumor WNK2, thus affecting cancer progression [ 101 , 107 , 109 , 117 – 119 ]. However, the inhibitory effect of these miRNAs on WNK expression can be released by the “sponge effect” of long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), such as lncRNA FTX, lncRNA H19 and circRNA circ_0001666 [ 109 , 118 , 119 ].…”