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 ◽  
...  

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.

Author(s):  
Francesco Palma ◽  
Alessandra Affinito ◽  
Silvia Nuzzo ◽  
Giuseppina Roscigno ◽  
Iolanda Scognamiglio ◽  
...  

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.


Author(s):  
Sarah Santiloni Cury ◽  
Diogo de Moraes ◽  
Paula Paccielli Freire ◽  
Grasieli de Oliveira ◽  
Douglas Venâncio Pereira Marques ◽  
...  

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and T10 vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, IL-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL6, CSF3, and IL8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these up-regulated genes, IL8 expression in NSCLC tissues was associated with worse prognosis and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.


2020 ◽  
Author(s):  
Damiano Scopetti ◽  
Danilo Piobbico ◽  
Cinzia Brunacci ◽  
Stefania Pieroni ◽  
Guido Bellezza ◽  
...  

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.


Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2075 ◽  
Author(s):  
José Francisco Noguera-Uclés ◽  
Laura Boyero ◽  
Ana Salinas ◽  
Juan Antonio Cordero Varela ◽  
Johana Cristina Benedetti ◽  
...  

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.


2020 ◽  
Vol 401 (3) ◽  
pp. 417-422 ◽  
Author(s):  
Yan-Bin Sun ◽  
Guang-Hao Sun ◽  
Shun Xu ◽  
Jing-Jing Xu

AbstractCirculating CD44+ cells have been identified as a prognostic marker for patients with non-small cell lung cancer (NSCLC). Serum tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) is involved in the pathophysiology of many cancers. However, no previous studies have shown the roles of sTRAIL in circulating CD44+ cells in the blood of NSCLC patients. We detected circulating CD44+ cells and sTRAIL levels in blood samples from NSCLC patients using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Anti-tumor roles of TRAIL in CD44+ cells were confirmed using a CCK-8 assay and mouse models. A higher number of circulating CD44+ cells were identified in NSCLC patients compared with healthy control individuals. In addition, we confirmed the anti-tumor roles and mechanisms of TRAIL in CD44+ cells both in vitro and in vivo. Our results indicate that (1) there is a negative correlation between sTRAIL and circulating CD44+ cells in NSCLC patients and (2) CD44+ cells have cancer stem cell properties and are more sensitive than CD44− cells to TRAIL.


2018 ◽  
Vol 104 (5) ◽  
pp. 338-343 ◽  
Author(s):  
Ying Ma ◽  
Shirong Kang ◽  
Xu Wu ◽  
Bateer Han ◽  
Zhiyong Jin ◽  
...  

Background: Pleural effusion is one of the complications of human non-small cell lung cancer (NSCLC). High mobility group box-1 protein (HMGB1) correlates highly with invasion and metastasis in multiple tumors. The aim of this study was to explore the clinical value of HMGB1 in NSCLC patients, and to investigate the role of HMGB1 in the development of pleural effusion. In addition, we also investigated the regulatory role of HMGB1 in the sensitivity of NSCLC cells to cisplatin. Methods: 46 NSCLC malignant pleural effusion (MPE) and 31 benign pleural effusion samples were quantitatively analyzed with Enzyme-Linked Immunosorbent Assay (ELISA) for cytokines, such as IL-1beta, IL-6, IL-8 and HMGB1. The HMGB1 expression in NSCLC tissues was examined with RT-qPCR and western blotting methods. Then the influence by HMGB1 on the chemosensitivity of lung cancer A549 cells was examined with MTT assay and colony forming assay for the A549 cells post the treatment with cisplatin or (and) HMGB1. Results: The results demonstrated that HMGB1 was up-regulated in the pleural effusion of NSCLC patients, along with the up-regulated levels of proinflammatory cytokines such as IL-6 and IL-8. And the up-regulation of HMGB1 was confirmed at both the mRNA and protein levels in the NSCLC tissues. Recombinant HMGB1 reduced the sensitivity of A549 cells to cisplatin in vitro. Conclusions: In conclusion, HMGB1 was up-regulated in the pleural effusion and tumor tissues of NSCLC patients. HMGB1 reduced the sensitivity of NSCLC A549 cells to cisplatin in vitro.


2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Shuang Tian ◽  
Ya-Nan Xing ◽  
Pu Xia

Circulating tumor cells can provide important diagnostic and prognostic information of the patients with non-small cell lung cancer (NSCLC). Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, has been used in various tumors, including NSCLC. In the present study, we isolated the circulating ALDH1+ tumor cells from the NSCLC patients using ALDH1 as a potential marker. Higher percentage of ALDH1+ tumor cells was identified in blood samples from the NSCLC patients compared with normal controls. ALDH1+ cells were correlated with the poor prognosis of these patients by using Kaplan–Meier analysis. In the last, the tumorigenic properties of ALDH1+ tumor cells were determined in vitro and in vivo by using sphere assay and xenograft tumor mouse models. Our in vitro and in vivo experiments demonstrated that ALDH1 could drive the stemness of circulating NSCLC cells. Circulating ALDH1+ cells could be used as a prognostic marker for NSCLC.


2020 ◽  
Vol 21 (11) ◽  
pp. 771-783
Author(s):  
Fannian Li ◽  
Haitao Li ◽  
Shuai Li ◽  
Baolei Lv ◽  
Junjie Shi ◽  
...  

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.


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