Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275/PROCA1/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma

Abstract

Background LINC00173 had been reported as a cisplatin (cis-diamminedichloroplatinum, DDP) chemotherapy-resistant inducer in small-cell lung cancer (SCLC) and lung squamous cell carcinoma (LUSC). This study aimed to display reverse data for LINC00173 as a DDP chemosensitivity-inducing factor in lung adenocarcinoma (LUAD). Methods LINC00173 was screened from the Gene Expression Omnibus database (GSE43493). The expression level of LINC00173 in LUAD tissues and cell lines was detected using in situ hybridization and quantitative reverse transcription–polymerase chain reaction. Colony formation, cell viability, half-maximal inhibitory concentration, flow cytometry, and xenograft mouse model were used to evaluate the role of LINC00173 in the chemosensitivity of LUAD to DDP. The mechanism of LINC00173 in DDP resistance by mediating miR-1275/PROCA1/ZFP36L2 axis to impair BCL2 mRNA stability was applied, and co-immunoprecipitation, chromatin immunoprecipitation, RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays were performed. Results LINC00173 downregulation in patients with DDP-resistant LUAD was correlated with poor prognosis. Further, LINC00173 expression was significantly reduced in DDP-resistant LUAD cells and DDP-treated human LUAD tissues. Suppressed LINC00173 expression in LUAD cells enhanced DDP chemoresistance in vivo and in vitro, while restored LINC00173 expression in DDP-resistant LUAD cells markedly regained chemosensitivity to DDP. Mechanistically, DDP-resistant LUAD cells activated PI3K/AKT signal and further elevated the c-Myc expression. The c-Myc, as an oncogenic transcriptional factor, bound to the promoter of LINC00173 and suppressed its expression. The reduced LINC00173 expression attenuated the adsorption of oncogenic miR-1275, downregulating the expression of miR-1275 target gene PROCA1. PROCA1 played a potential tumor-suppressive role inducing cell apoptosis and DDP chemosensitivity via recruiting ZFP36L2 to bind to the 3′ untranslated region of BCL2, reducing the stability of BCL2 mRNA and thus activating the apoptotic signal. Conclusions This study demonstrated a novel and critical role of LINC00173. It was transcriptionally repressed by DDP-activated PI3K/AKT/c-Myc signal in LUAD, promoting DDP-acquired chemotherapeutic resistance by regulating miR-1275 to suppress PROCA1/ZFP36L2-induced BCL2 degradation, which led to apoptotic signal reduction. These data were not consistent with the previously described role of LINC00173 in SCLC or LUSC, which suggested that LINC00173 could play fine-tuned DDP resistance roles in different pathological subtypes of lung cancer. This study demonstrated that the diminished expression of LINC00173 might serve as an indicator of DDP-acquired resistance in LUAD.

Expression of Tumor Suppressor FHIT Is Regulated by the LINC00173-SNAIL Axis in Human Lung Adenocarcinoma

“…Using this dataset, we performed Kaplan-Meier analysis and found that the prognosis of the patient group with low LINC00173 expression, high SNAIL expression, and low FHIT expression was significantly poor (p = 0.0116, 0.0221, and 0.0074, respectively, Figure 4A). This is consistent with previous reports showing that LINC00173 and FHIT act as tumor suppressors in lung adenocarcinoma [8,46,52]. This dataset was then used for correlation analysis between the expression of these genes.…”

“…LINC00173 is associated with various types of human cancer in a cell context-dependent manner [7,9,10,46]. Among them, we focused on the non-small cell lung cancer, lung adenocarcinoma, in which LINC00173 acts as a suppressor of tumorigenesis and tumor progression [8,46]. We selected the A549 cell line derived from human lung adenocarcinoma for the analysis and obtained its expression profile under our culture conditions by RNA-seq.…”

“…To analyze the expression levels of each LINC00173 variant, we used our RNA-seq-derived expression profile of A549 cells and found that LINC00173-205 had the highest expression level, followed by LINC00173-203 (Figure S1B). Only LINC00173-203, and not LINC00173-205, has been previously functionally analyzed [8,[49][50][51] (note that variant LINC00173-203 registered in the Ensembl database is identical to variant NR_027345.1, also called LINC00173-TSV1, registered in the NCBI database). Based on these expression profiles and previous reports, we decided to focus on LINC00173-203 (we hereafter refer to LINC00173-203 as LINC00173).…”

“…It is involved in promoting tumorigenesis and tumor progression in squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, and colorectal cancer [7]. In contrast, it also suppresses tumorigenesis and tumor progression in lung adenocarcinoma [8], cervical cancer [9], and acute myeloid leukemia [10]. This cell context-dependent action of LINC00173 can be attributed to its varied molecular functions; it acts as a molecular sponge of miRNAs to stabilize the mRNAs and enhance the expression of target genes [7], and it selectively binds to target proteins, such as DNMT1 [10] and HNRNPA2B1 [11], to modulate their downstream pathways.…”

LINC00460 knockdown sensitizes cervical cancer to cisplatin by downregulating TGFBI

“…The development of DDP resistance impedes its application in cancer treatment. Previous studies have shown that lncRNAs may act as key targets in regulating DDP sensitivity (Chi et al., 2018; Tao et al., 2023; Zhang et al., 2019; Zhu et al., 2022). In present study, TCGA dataset and RT‐qPCR analyses showed that LINC00460 was highly expressed in cervical cancer tumor tissues and cell lines, and upregulation of LINC00460 might serve as a prognostic factor of cervical cancer patients.…”