Cisplatin-resistant Non-small Cell Lung Cancer Research Articles

Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3β/MCL-1 pathway.

Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC. This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3β by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis. In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3β was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3β and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells. Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3β/MCL-1 pathway.

Metabolic features of cancer cells impact immunosurveillance

BackgroundTumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the...

KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer.

Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.

Cancer-associated fibroblasts secreted miR-103a-3p suppresses apoptosis and promotes cisplatin resistance in non-small cell lung cancer.

Background: The cisplatin resistance of non-small cell lung cancer (NSCLC) patients results in low response rate and overall survival rate. Exosomes contribute to pathological processes of multiple cancers.Objective: In this study, we explored the function and mechanisms of exosomal miR-103a-3p derived from cancer-associated fibroblast (CAF) in cisplatin resistance in NSCLC.Results: MiR-103a-3p was highly expressed in CAFs and CAF exosomes, and exosomal miR-103a-3p derived from CAFs in NSCLC. CAFs exosomes co-cultured with NSCLC cells promoted miR-103a-3p expression both in NSCLC cells and its exosomes. Functional experiments showed that exo-miR-103a-3p derived from CAFs promoted cisplatin resistance and inhibited apoptosis in NSCLC cells. Pumilio2 (Pum2) bound with miR-103a-3p in cytoplasm and nucleus, and facilitated packaging into CAF-derived exosomes in NSCLC cells. Further analysis showed Bak1 was a direct target of miR-103a-3p, and miR-103a-3p accelerated cisplatin resistance in NSCLC cells via Bak1 downregulation. In vivo tumorigenesis assay showed CAF-derived exosomal miR-103a-3p enhanced cisplatin resistance and inhibited cell apoptosis in NSCLC.Conclusion: Our study revealed that CAFs-derived exosomal miR-103a-3p promoted cisplatin resistance by suppressing apoptosis via targeting Bak1, which provided a potential therapeutic target for cisplatin resistance in NSCLC.

Mir-126-5p Promotes Cisplatin Sensitivity of Non-Small-Cell Lung Cancer by Inhibiting ADAM9.

Objective The aim of the study was to investigate molecular mechanisms underlying the role of miR-126-5p in cisplatin (DDP) sensitivity of non-small-cell lung cancer (NSCLC). Methods The expression of miR-126-5p and ADAM9 in NSCLC cancer tissues and adjacent tissues, cisplatin-sensitive and drug-resistant NSCLC patient tissues, human normal lung epithelial cells (BESA-2B), human lung adenocarcinoma cell lines A549 and H1560, and cisplatin-resistant mutant cell lines A549/DDP and H1560/DDP was detected by qRT-PCR. After overexpression of miR-126-5p or ADAM9 in A549/DDP and H1560/DDP, MTT and clone formation were used to detect the cell proliferation ability of each treatment group. Flow cytometry was used to detect changes in cell apoptosis. The protein expression of ADAM9 and key molecules of PTEN/PI3K/Akt pathways in cells was measured by western blot. Results Compared with NSCLC adjacent tissues and NSCLC cisplatin-sensitive tissues, miR-126-5p expression was downregulated in NSCLC tissues and cisplatin-resistant NSCLC tissues and ADAM9 was upregulated. qRT-PCR further detected that miR-126-5p was downregulated in A549, H1560, and their cisplatin-resistant strains A549/DDP and H1560/DDP, while ADAM9 was upregulated. Moreover, overexpression of miR-126-5p inhibited A549/DDP and H1560/DDP cell proliferation and promoted cell apoptosis. The results of dual luciferase showed that miR-126-5p targeted and negatively regulated ADAM9. We also found that overexpression of ADAM9 could reverse the effects of miR-126-5p on NSCLC cell proliferation, apoptosis, and cisplatin sensitivity, and this effect may be achieved by inhibiting the activity of the PTEN/PI3K/Akt signaling pathway. Conclusion Our data indicated that miR-126-5p may negatively regulate ADAM9 to promote the sensitivity of clinical DDP treatment of NSCLC and be a potential therapeutic target for NSCLC treatment.

Down-Regulating the Expression of miRNA-21 Inhibits the Glucose Metabolism of A549/DDP Cells and Promotes Cell Death Through the PI3K/AKT/mTOR/HIF-1α Pathway.

miRNA-21 is a single-stranded non-coding RNA that is highly expressed in a variety of tumor cells. It participates in tumor cell proliferation, metabolism, metastasis, and drug resistance. Here, we tested the potential mechanism of miRNA-21 in cisplatin-resistant non-small cell lung cancer A549/DDP (human lung adenocarcinoma drug-resistant cell line) cells. A549 and A549/DDP RNAs were sequenced to show that miRNA-21 was highly expressed in the latter, and this was verified by qRT-PCR. In addition, we found that miRNA-21 combined with cisplatin can significantly inhibit glycolysis and glycolysis rate-limiting enzyme protein expression in A549/DDP cells. We also found that miRNA-21 combined with cisplatin can promote A549/DDP cell death. Further investigations showed that miRNA-21 combined with cisplatin caused excessive inactivation of the pI3K/AKT/mTOR/HIF-1α signaling pathway in cisplatin-resistant A549/DDP cells. Hence, reduction of the expression of miRNA-21 in combination with cisplatin chemotherapy may effectively improve the therapeutic effect on patients with non-small cell lung cancer, and this may provide a theoretical basis for the treatment of this disease.

SNRPB is a mediator for cellular response to cisplatin in non-small-cell lung cancer.

The small nuclear ribonucleoprotein polypeptides B And B' (SNRPB) is a core component of spliceosome and plays a key role in pre-mRNA splicing. Emerging evidence suggests that it involves in the development of several types of cancer. Our previous study has demonstrated SNRPB is highly expressed in non-small-cell lung cancer (NSCLC) and functions as an oncogene. However, whether SNRPB contributes to cisplatin resistance in NSCLC is still unknown. In this study, we found that SNRPB negatively regulates cisplatin resistance in NSCLC cells. Knocking out of SNRPB could significantly decrease cisplatin-induced cell growth inhibition, cell cycle arrest and apoptosis in H1299 cells. However, enforced expression of SNRPB in H460 cells can markedly promote cisplatin-induced cell growth inhibition, cell cycle arrest and apoptosis. Our results also indicate that overexpression of SNRPB enhances the inhibitory effects of cisplatin on H460 cell-mediated xenograft tumors. Our results suggest that SNRPB may be a prediction marker for NSCLC patients in response to cisplatin-based chemotherapy.

MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung cancer

BackgroundIn the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation.MethodsmiRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines.ResultsDifferential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours.ConclusionsThis study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.

Exploitation of the vitamin A/retinoic acid axis depletes ALDH1-positive cancer stem cells and re-sensitises resistant non-small cell lung cancer cells to cisplatin

Despite advances in personalised medicine and the emerging role of immune checkpoints in directing treatment decisions in subsets of lung cancer patients, non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related deaths worldwide. The development of drug resistance plays a key role in the relapse of lung cancer patients in the clinical setting, mainly due to the unlimited renewal capacity of residual cancer stem cells (CSCs) within the tumour cell population during chemotherapy. In this study, we investigated the function of the CSC marker, aldehyde dehydrogenase (ALDH1) in retinoic acid cell signalling using an in vitro model of cisplatin resistant NSCLC. The addition of key components in retinoic acid cell signalling, all-trans retinoic acid (ATRA) and retinol to cisplatin chemotherapy, significantly reduced ALDH1-positive cell subsets in cisplatin resistant NSCLC cells relative to their sensitive counterparts resulting in the re-sensitisation of chemo-resistant cells to the cytotoxic effects of cisplatin. Furthermore, combination of ATRA or retinol with cisplatin significantly inhibited cell proliferation, colony formation and increased cisplatin-induced apoptosis. This increase in apoptosis may, at least in part, be due to differential gene expression of the retinoic acid (RARα/β) and retinoid X (RXRα) nuclear receptors in cisplatin-resistant lung cancer cells. These data support the concept of exploiting the retinoic acid signalling cascade as a novel strategy in targeting subsets of CSCs in cisplatin resistant lung tumours.

Effect of Nano-Platinum on Proliferation and Apoptosis of Non-Small Cell Lung Cancer Cells via P53 Pathway.

This paper studies the non-small cell lung cancer with interventional treatment of polyethylene imine-coated platinum nanoclusters. The relationship between the inhibition of non-small cell lung cancer cell proliferation, apoptosis, and the expression of its related apoptotic protein p53. Apoptosis experiments were applied was used to detect the effect of nanoplatin on A549 cells. Western blot was used to detect the expression of p53 protein in A549 cells after nanoplatin treatment. We co-cultured nanoplatin with cells for 4 hours and performed nuclear staining. Observed by laser confocal microscopy, we found that nanoplatin can enter the nucleus and cytoplasm of non-small cell lung cancer A549 cells, and the phenomenon of drug entering the nucleus is very obvious. Treatment of non-small cell lung cancer with A549 cells at different concentrations of nanoplatin for 24 hours, with the increase of the concentration, the proliferation inhibition rate of non-small cell lung cancer gradually increased. Treatment of cisplatin-resistant non-small cell lung cancer cells with different concentrations of nanoplatin for 24 hours, as the concentration increases, the proliferation inhibition rate of non-small cell lung cancer gradually increases. After treatment of A549 cells with different concentrations of nanoplatin for 24 hours, the apoptosis rate of A549 cells gradually increased with the increase of drug concentration. Finally, we conclude that nanoplatin has not only inhibitory and pro-apoptotic effects on non-small cell lung cancer cells, but also fluorescent labeling. Compared with cisplatin, nanoplatin can significantly inhibit the proliferation of non-small cell lung cancer cells and overcome its cisplatin resistance. The p53-related signaling pathway may participate in the process of apoptosis and reverse the process of cisplatin resistance, but the specific mechanism and whether there are other signaling pathways involved Further research is needed.

Knock-down of microRNA miR-556-5p increases cisplatin-sensitivity in non-small cell lung cancer (NSCLC) via activating NLR family pyrin domain containing 3 (NLRP3)-mediated pyroptotic cell death

ABSTRACT MicroRNAs (miRNAs) are small non-coding RNAs that are closely associated with cancer progression and drug resistance, however, up until now, the involvement of miR-556-5p in regulating cisplatin-sensitivity in non-small cell lung cancer (NSCLC) has not been studied. In the present study, we found that miR-556-5p was significantly upregulated in the cisplatin-resistant NSCLC (CR-NSCLC) patients’ tissues and cells, instead of the corresponding cisplatin-sensitive NSCLC (CS-NSCLC) tissues and cells. Further experiments validated that knock-down of miR-556-5p suppressed cell viability and tumorigenesis, and induced cell apoptosis in the cisplatin-treated CR-NSCLC cells, and conversely, upregulation of miR-556-5p increased cisplatin-resistance in CS-NSCLC cells. Interestingly, miR-556-5p ablation triggered pyroptotic cell death in cisplatin-treated CR-NSCLC cells via upregulating NLRP3, and the promoting effects of miR-556-5p silence on cisplatin-sensitivity in CR-NSCLC cells were abrogated by both cell pyroptosis inhibitor NSA and NLRP3 downregulation. Taken together, this study firstly evidenced that induction of NLRP3-mediated cell pyroptosis by miR-556-5p downregulation was effective to increase cisplatin-sensitivity in NSCLC, which provided new therapy strategies to overcome chemo-resistance for NSCLC patients in clinic.

Targeting the miR-6734-3p/ZEB2 axis hampers development of non-small cell lung cancer (NSCLC) and increases susceptibility of cancer cells to cisplatin treatment

ABSTRACT The unclear pathogenesis mechanisms and resistance of cancer cells to chemical drugs serious limits the development of effective treatment strategies for non-small cell lung cancer (NSCLC). In this study, we managed to investigate this issue, and identify potential cancer associated biomarkers for NSCLC diagnosis, prognosis and treatment. This study found that miR-6734-3p was downregulated in both NSCLC clinical specimens (tissues and serum) and cells, compared to the normal tissues and cells. Next, upregulation of miR-6734-3p inhibited cancer formation and progression in NSCLC cells in vitro and in vivo. Conversely, miR-6734-3p ablation had opposite effects and facilitated NSCLC development. In addition, miR-6734-3p bound to the 3ʹ untranslated region (3ʹUTR) of zinc finger E-box binding homeobox 2 (ZEB2) mRNA to suppress its expressions in NSCLC cells. Interestingly, the inhibiting effects of miR-6734-3p overexpression on NSCLC progression were abrogated by upregulating ZEB2. Furthermore, both upregulated miR-6734-3p and silencing of ZEB2 increased cisplatin-sensitivity in cisplatin-resistant NSCLC (CR-NSCLC) cells. Taken together, miR-6734-3p played an anti-tumor role to hinder cancer development and enhanced the cytotoxic effects of cisplatin treatment on NSCLC cells by downregulating ZEB2.

Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2.

Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC).Methods: NSCLC cells were subjected to either normoxic or hypoxic conditions to assess cell survival and changes in the expression levels of key proteins. Comparative proteomics were performed to identify exosomal PKM2 in normoxic or hypoxic cisplatin-resistant NSCLC cells-derived exosomes. Functions of hypoxia induced-exosomal PKM2 in promoting cisplatin resistance to NSCLC cells were evaluated both in vitro and in vivo experiments and the molecular mechanisms of hypoxia induced-exosomal PKM2 were demonstrated using flow cytometry, immunoblotting, oxidative stress detection and histological examination. A series of in vitro experiments were performed to evaluate the function of hypoxia-induced exosomes on cancer-associated fibroblasts (CAFs).Results: Hypoxia exacerbated the cisplatin resistance in lung cancer cells due to the increased expression of PKM2 that was observed in the exosomes secreted by hypoxic cisplatin-resistance cells. We identified that hypoxia-induced exosomal PKM2 transmitted cisplatin-resistance to sensitive NSCLC cells in vitro and in vivo. Mechanistically, hypoxia-induced exosomal PKM2 promoted glycolysis in NSCLC cells to produce reductive metabolites, which may neutralize reactive oxygen species (ROS) induced by cisplatin. Additionally, hypoxia-induced exosomal PKM2 inhibited apoptosis in a PKM2-BCL2-dependent manner. Moreover, hypoxia-induced exosomal PKM2 reprogrammed CAFs to create an acidic microenvironment promoting NSCLC cells proliferation and cisplatin resistance.Conclusions: Our findings revealed that hypoxia-induced exosomes transmit cisplatin resistance to sensitive NSCLC cells by delivering PKM2. Exosomal PKM2 may serve as a promising biomarker and therapeutic target for cisplatin resistance in NSCLC.

Retraction notice to 'The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells' [EBioMedicine 35 (2018) 204-221

Retraction notice to 'The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells' [EBioMedicine 35 (2018) 204-221

CAFs-Derived Exosomal miRNA-130a Confers Cisplatin Resistance of NSCLC Cells Through PUM2-Dependent Packaging.

PurposeChemoresistance is a significant barrier to the treatment and management of non-small cell lung cancer (NSCLC). Exosomes play an essential role in intercellular communication. Understanding the mechanism underlying the role of tumor stroma, especially cancer-associated fibroblasts (CAFs), during chemoresistance would significantly contribute to the clinical application of chemotherapy agents.ResultsIn this study, we demonstrated that NSCLC-derived CAFs were innately resistant to cisplatin treatment and CAFs-conditioned medium significantly promoted the survival rate of NSCLC cells after cisplatin treatment. Additionally, CAFs-derived exosomes were taken up by NSCLC cells. Moreover, exosomal miRNA-130a was transferred from CAFs to recipient NSCLC cells and knockdown of miRNA-130a reversed the effect of CAFs-derived exosomes during chemoresistance of NSCLC cells. Furthermore, pumilio homolog 2 (PUM2), a RNA-binding protein, mediated the packaging of miRNA-130a into exosomes. The overexpression and knockdown of PUM2 promoted and inhibited tumor growth of xenograft mice, respectively.ConclusionTaken together, these results suggest that CAFs-derived exosomes confer cisplatin resistance of NSCLC cells through transferring miRNA-130a and that PUM2 is a critical factor for packaging miRNA-130a into exosomes. This study indicates that CAFs-derived exosomal miRNA-130a may be a potential therapeutic target for cisplatin resistance in NSCLC.

Unprecedented collateral sensitivity for cisplatin-resistant lung cancer cells presented by new ruthenium organometallic compounds

Ru compounds exhibit collateral sensitivity in cisplatin-resistant NSCLC and increase cisplatin activity by inhibiting efflux pumps.

Tachyplesin induces apoptosis in non-small cell lung cancer cells and enhances the chemosensitivity of A549/DDP cells to cisplatin by activating Fas and necroptosis pathway.

Cisplatin has strong broad-spectrum anticancer activity and is one of the most effective anticancer drugs currently used. The clinical application of cisplatin has led to the resistance of cancer cells to cisplatin. Tachyplesin is an active, natural marine peptide with antitumour activity. In the present study, we investigated whether tachyplesin can be used in non-small cell lung cancer (NSCLC) A549 and H460 cells as well as the cisplatin-resistant human A549/DDP NSCLC cell line. The results revealed that tachyplesin treatment significantly inhibited proliferation and induced apoptosis in A549 and H460 cells and the combination of tachyplesin and cisplatin significantly suppressed migration and improved sensitivity to cisplatin in A549/DDP cells. Further mechanistic examination revealed that tachyplesin induced apoptosis in A549/DDP cells by increasing Fas, FasL and p-RIPK1 levels. These results indicated that tachyplesin induces lung cancer death by activating the Fas, mitochondrial and necroptosis pathways. Tachyplesin could be developed as a candidate drug for cisplatin-resistant NSCLC.

A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC)

BackgroundCisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated.MethodsCell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3′ untranslated region (3’UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues.ResultsHere we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo.ConclusionsAnalysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic.

Pseudogene KRT17P3 drives cisplatin resistance of human NSCLC cells by modulating miR-497-5p/mTOR.

Chemoresistance is a major obstacle in non–small cell lung cancer (NSCLC) treatment. The pseudogene keratin 17 pseudogene 3 (KRT17P3) has been previously shown to be upregulated in lung cancer tissues of patients with cisplatin resistance. In the present study, RT‐qPCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin‐resistant and 32 cisplatin‐sensitive patients. We found that the plasma level of KRT17P3 is upregulated in cisplatin‐resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR‐497‐5p and relieves the binding of miR‐497‐5p to its target gene mTOR. Rescue experiments validated the functional interaction between KRT17P3, miR‐497‐5p, and mTOR. Taken together, our findings indicate that KRT17P3/miR‐497‐5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin‐resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin.

RING finger protein 38 induces the drug resistance of cisplatin in non-small-cell lung cancer.

Cisplatin resistance of non-small-cell lung cancer (NSCLC) needs to be well elucidated. RING finger protein (RNF38) has been proposed as a biomarker of NSCLC poor prognosis. However, its role in drug resistance in NSCLC is poorly understood. RNF38 expression was detected in normal lung epithelial cell and four NSCLC cell lines. RNF38 was stably overexpressed in A549 and H460 cells or silenced in H1975 and cisplatin-resistant A549 cells (A549-CDDP resistant) using lentiviral vectors. RNF38 expression levels were determined using quantitative real-time polymerase chain reaction and western blotting analysis. Cell viability in response to different concentrations of cisplatin was evaluated by Cell Counting Kit-8 assay. RNF38 expression levels were markedly elevated in NSCLC cells and cells harboring high RNF38 were less sensitive to cisplatin. Overexpression of RNF38 reduced, while RNF38 silencing increased the drug sensitivity of cisplatin in NSCLC cells. Cisplatin-resistant cells expressed high RNF38 level. RNF38 silencing promoted cell apoptosis and enhanced the drug sensitivity of cisplatin in cisplatin-resistant NSCLC cells. These findings indicate that RNF38 might induce cisplatin resistance of NSCLC cells via promoting cell apoptosis and RNF38 could be a novel target for rectify cisplatin resistance in NSCLC cases.