Increased MALAT1 expression contributes to cisplatin resistance in non‑small cell lung cancer

Abstract

Cisplatin-based chemotherapy is commonly used for the clinical treatment of patients with non-small cell lung cancer (NSCLC). However, the anti-tumor efficacy of cisplatin is limited by poor clinical response and the development of chemoresistance. At present, the underlying mechanism for cisplatin resistance remains unclear. In the present study, it was identified that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA that has been demonstrated to function as an oncogene, was increased in tumor tissues from patients with cisplatin-resistant NSCLC. In addition, the MALAT1 level was increased in A549rCDDP cells compared with the parental A549 cells. Silencing of MALAT1 sensitized A549rCDDP cells to cisplatin treatment, while overexpression of MALAT1 in A549 cells decreased their sensitivity towards cisplatin. Through analysis of the gene expression in patient samples, a decrease in miR-145 and an increase in Kruppel-like factor 4 (KLF4) in tumor tissues compared with adjacent normal tissues was observed. A negative association between MALAT1 and miR-145 was also identified in A549 cells and A549rCDDP cells. Furthermore, reverse transcription quantitative polymerase chain reaction and western blotting identified that KLF4 was positively and negatively regulated by MALAT1 and miR-145, respectively. The direct regulatory association between MALAT1 and miR-145 and the target gene KLF4 was additionally confirmed using a luciferase reporter assay. Knockdown of MALAT1 reversed cisplatin resistance in A549rCDDP cells. Taken together, these data indicated that MALAT1 decreased the sensitivity of NSCLC to cisplatin via the regulation of miR-145 and KLF4.

MiR‐145 in cancer therapy resistance and sensitivity: A comprehensive review

“…Kruppel‐like factor 4 (KLF4) is a transcription factor expressed in various human tissues, which controls cell reprogramming and sustains stemness maintenance 64 . LncRNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) contributed to cisplatin resistance by regulating the miR‐145/KLF4 axis in NSCLC 65 . Likewise, lncRNA ROR sponged miR‐145 to prevent OCT4, SOX2 and Nanog in colon CSC, thereby increasing the stem cell phenotype, and then enhanced chemoresistance to cisplatin and paclitaxel 66 (Figure 3).…”

<p>lncRNA MALAT1 Promotes EMT Process and Cisplatin Resistance of Oral Squamous Cell Carcinoma via PI3K/AKT/m-TOR Signal Pathway</p>

“…Recently, MALAT1 has been reported as a chemotherapeutic resistant factor in various cancers, such as colorectal cancer, 27 lymphoma, 28 glioblastoma, 29 ovarian cancer, and lung cancer. 30,31 Therefore, we assumed that MALAT1 might play an important role in DDP resistance of OSCC.…”

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

“…In NSCLC the expression of KLF4 is negatively regulated by various microRNAs: miR-25, miR-103, miR-145 and miR-3120-5p [ 69 , 73 , 74 , 75 ]. KLF4 expression is positively regulated by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA) that has been demonstrated to function as an oncogene [ 74 ]. This regulation is indirect as MALAT1 directly targets miR-145 and in this way it reduces the inhibitory effects of miR-145 on KLF4 activity [ 74 ].…”