miR-365a-5p suppresses gefitinib resistance in non-small-cell lung cancer through targeting PELI3

2020 ◽  
Vol 21 (11) ◽  
pp. 771-783
Author(s):  
Fannian Li ◽  
Haitao Li ◽  
Shuai Li ◽  
Baolei Lv ◽  
Junjie Shi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Signaling Axis ◽  
Nsclc Patients ◽  
Gefitinib Resistance

Aim: Demonstrate the function of dysregulated miR-365a-5p–PELI3 signaling axis in the generation of gefitinib resistance during treatment for non-small-cell lung cancer (NSCLC). Patients & methods: All the NSCLC patients who participated in this research were recruited from the Second Hospital of Hebei Medical University. PC9 cells and PC9GR cells were cultured for in vitro experiments. Results: Patients who were primary resistant to EGFR-tyrosine kinase inhibitor had lower miR-365a-5p levels. MiR-365a-5p directly targeted PELI3 mRNA. MiR-365a-5p overexpression enhanced the function of gefitinib in inhibiting cell viability. Tumor growth was suppressed through miR-365a-5p in nude mice. Conclusion: Dysregulated miR-365a-5p–PELI3 signaling axis triggered the generation of gefitinib resistance in NSCLC.

scholarly journals Epigenetic control of INSL4 promotes cell growth and invasiveness in Non-Small-Cell Lung Cancer

2020 ◽  
Author(s):  
Damiano Scopetti ◽  
Danilo Piobbico ◽  
Cinzia Brunacci ◽  
Stefania Pieroni ◽  
Guido Bellezza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Relaxin Family ◽  
Nsclc Patients

Abstract Background Non-Small Cell Lung Cancer accounts for 80–85% of all forms of Lung Cancer as leading cause of cancer-related death in human. Despite remarkable advances in the diagnosis and therapy of Lung Cancer, no significant improvements have thus far been achieved in terms of patients’ prognosis. Here, we investigated the role of INSL4 – a member of the relaxin family –in NSCLC.Methods We permanently overexpressed INSL4 in NSCLC cells in vitro to analyse the growth rate and the tumourigenic features. We further investigated the signalling pathways engaged in INSL4 overexpressing cells and the tumour growth ability by studying the tumour development in a patient derived tumour xenograft mouse model. Results We found a cell growth promoting effect by INSL4 overexpression in vitro in H1299 cells and in vivo in NOD/SCID mice. Surprisingly, in NSCLC-A549 cells, stable INSL4 overexpression has not showed similar effect, despite has an INSL4-mRNA expressed up to 22.000 fold more respect H1299. The INSL4-mRNA analysis of eight different NSCLC-derived cell lines, has revealed a great discrepancy between the amount of INSL4-mRNA and specific protein. Notably, similar result has been observed in studied NSCLC patients analysing and comparing INSL4 mRNA and protein expression. However, in a cohort of NSCLC patients, we found a significant inverse correlation between INSL4 expression and Overall Survival.Conclusions By combining the results from the in vitro and in vivo models and in silico analysis in patients whose NSCLCs adenocarcinoma spontaneously expressed high levels of INSL4 our results suggest that epigenetic modifications that affect INSL4 does not allow to assess precision therapy in selected patients without consider protein INSL4 amount.

scholarly journals miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer

2020 ◽  
Author(s):  
Francesco Palma ◽  
Alessandra Affinito ◽  
Silvia Nuzzo ◽  
Giuseppina Roscigno ◽  
Iolanda Scognamiglio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Synthetic Lethality ◽  
Small Cell ◽  
In Vitro Assays ◽  
Prognostic Impact ◽  
Small Cell Lung ◽  
Nsclc Patients

Abstract Lung cancer is still the leading cause of death by cancer worldwide despite advances both in its detection and therapy. Multiple oncogenic driver alterations have been discovered, opening the prospective for new potential therapeutic targets. Among them, KRAS mutations represent the most frequent oncogene aberrations in non-small cell lung cancer (NSCLC) patients with a negative prognostic impact, but effective therapies targeting KRAS are not well characterized yet. Here, we demonstrate that the microRNA miR-34c-3p is a positive prognostic factor in KRAS-mutated NSCLC patients. Firstly, looking at the TGCA dataset, we found that high miR-34c-3p expression correlated with longer survival of KRAS-mutated NSCLC patients. In vitro assays on immortalized and patient-derived primary NSCLC cells revealed that miR-34c-3p overexpression increased apoptosis and lowered proliferation rate in KRASmut cells. Computational analysis and in vitro assays identified CDK1, one of the most promising lethal targets for KRAS-mutant cancer, as a target of miR-34c-3p. Moreover, the combination of CDK1 inhibition (mediated by RO3306) and miR-34c-3p overexpression resulted in an additive effect on the viability of KRASmut-expressing cells. Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.

scholarly journals Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592199297
Author(s):  
Lingzhi Hong ◽  
Jianjun Zhang ◽  
John V. Heymach ◽  
Xiuning Le
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Development Program ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping ( METex14) alterations occur in 3–4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.

scholarly journals Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zhe Liu ◽  
Liang Ma ◽  
Yiming Sun ◽  
Wenying Yu ◽  
Xue Wang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Resistance Rate ◽  
Small Cell ◽  
In Vivo Studies ◽  
Small Cell Lung ◽  
Gefitinib Resistance

AbstractLung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.

scholarly journals A Radioresponse-Related lncRNA Biomarker Signature for Risk Classification and Prognosis Prediction in Non-Small-Cell Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jiahang Song ◽  
Shuming Zhang ◽  
Yuanyuan Sun ◽  
Junjie Gu ◽  
Ziqi Ye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Risk Model ◽  
Differential Expression Analysis ◽  
Small Cell ◽  
In Vitro Assays ◽  
Small Cell Lung ◽  
Nsclc Patients

Purpose. Radiotherapy resistance is now recognized as the major obstacle to the effective therapeutic management of non-small-cell lung cancer (NSCLC). As a single biomarker has limited effect in stratifying NSCLC patients, this research aimed to identify long non-coding RNAs (lncRNAs) correlated with radiotherapy response to ameliorate forecast of NSCLC prognosis. Methods. In a cohort of NSCLC patients with radiotherapy history (n = 96) from TCGA, genetic data of lncRNA expression profiling were performed. To identify radioresponse-related lncRNA sets which dysregulated significantly between radiosensitive (RS) and radioresistant (RR) groups, differential expression analysis was carried out. Cox relative regression was implemented to set up a radioresponse-related risk model. Moreover, we adopted survival analysis to measure the predictive potentiality of the prognosis model. Results. Four radioresponse-related lncRNAs (CASC19, LINC01977, LINC02471, and MAGI2-AS3) were screened to create a prognostic signature. Then, we described a lncRNA signature-based regulatory network and explored the correlation of the immune microenvironment and the signature. Additionally, in vitro assays uncovered inhibition of LINC01977 weakened radioresistance of NSCLC cells. Conclusion. We provided a novel radioresponse-related lncRNAs signature with excellent clinical potency for an effective prognostic forecast of patients.

scholarly journals The Roles of Imprinted SLC22A18 and SLC22A18AS Gene Overexpression Caused by Promoter CpG Island Hypomethylation as Diagnostic and Prognostic Biomarkers for Non-Small Cell Lung Cancer Patients

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2075 ◽  
Author(s):  
José Francisco Noguera-Uclés ◽  
Laura Boyero ◽  
Ana Salinas ◽  
Juan Antonio Cordero Varela ◽  
Johana Cristina Benedetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Prognostic Biomarkers ◽  
Gene Copy ◽  
Small Cell Lung ◽  
Nsclc Patients

Genomic imprinting is a process that involves one gene copy turned-off in a parent-of-origin-dependent manner. The regulation of imprinted genes is broadly dependent on promoter methylation marks, which are frequently associated with both oncogenes and tumor suppressors. The purpose of this study was to assess the DNA methylation patterns of the imprinted solute-carrier family 22 member 18 (SLC22A18) and SLC22A18 antisense (SLC22A18AS) genes in non-small cell lung cancer (NSCLC) patients to study their relevance to the disease. We found that both genes were hypomethylated in adenocarcinoma and squamous cell carcinoma patients. Due to this imprinting loss, SLC22A18 and SLC22A18AS were found to be overexpressed in NSCLC tissues, which is significantly more evident in lung adenocarcinoma patients. These results were validated through analyses of public databases of NSCLC patients. The reversed gene profile of both genes was achieved in vitro by treatment with ademetionine. We then showed that high SLC22A18 and SLC22A18AS expression levels were significantly associated with worsening disease progression. In addition, low levels of SLC22A18AS were also correlated with better overall survival for lung adenocarcinoma patients. We found that SLC22A18 and SLC22A18AS knockdown inhibits cell proliferation in vitro. All these results suggest that both genes may be useful as diagnostic and prognostic biomarkers in NSCLC, revealing novel therapeutic opportunities.

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