Non-small-cell lung cancer and miRNAs: novel biomarkers and promising tools for treatment

Lung cancer is the leading cause of cancer-related death worldwide, with approximately 80–85% of cases being non-small-cell lung cancer (NSCLC). The miRNAs are small non-coding RNAs that regulate gene expression at a post-transcriptional level by either degradation or inhibition of the translation of target genes. Evidence is mounting that miRNAs exert pivotal effects in the development and progression of human malignancies, including NSCLC. A better understanding of the role that miRNAs play in the disease will contribute to the development of new diagnostic biomarkers and individualized therapeutic tools. In the present review, we briefly describe the role of miRNAs in NSCLC as well as the possible future of these discoveries in clinical applications.

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CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Cell Communication and Signaling ◽

10.1186/s12964-020-00571-4 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Hang Li ◽

Jun Che ◽

Mian Jiang ◽

Ming Cui ◽

Guoxing Feng ◽

...

Keyword(s):

Lung Cancer ◽

Estrogen Receptor ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Target Genes ◽

Small Cell ◽

Small Cell Lung

Abstract Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

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HDAC3 regulates senescence and lineage-specific transcriptional programs in non-small cell lung cancer

10.1101/2020.10.14.338590 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lillian J. Eichner ◽

Stephanie D. Curtis ◽

Sonja N. Brun ◽

Joshua T. Baumgart ◽

Debbie S. Ross ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Target Genes ◽

Transcriptional Profiling ◽

Hdac Inhibitors ◽

Small Cell ◽

Small Cell Lung

SummaryTranscriptional deregulation is a common feature of many cancers, which is often accompanied by changes in epigenetic controls. These findings have led to the development of therapeutic agents aimed at broad modulation and reprogramming of transcription in a variety of cancers. Histone Deacetylase 3, HDAC3, is one of the main targets of HDAC inhibitors currently in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we define the role of HDAC3 in two genetic engineered models of the most common subtypes of Kras-driven Non-Small Cell Lung Cancer (NSCLC), KrasG12D, STK11−/− (KL) and KrasG12D, p53−/− (KP), where we found that HDAC3 is strongly required for tumor growth of both genotypes in vivo. Transcriptional profiling and mechanistic studies revealed that HDAC3 represses p65 RelA/NF-kB-mediated induction of the Senescence Associated Secretory Program (SASP). Additionally, HDAC3 was found to cooperate with the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. Leveraging observations about one HDAC3/NKX2-1 common target, FGFR1, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras mutant cancer cells develop resistance to the MEK inhibitor Trametinib, and this can be rescued by treatment with the Class I HDAC inhibitor Entinostat. These unexpected findings reveal new roles for HDAC3 in proliferation control in tumors in vivo and identify specific therapeutic contexts for the utilization of HDAC3 inhibitors, whose ability to mechanistically induce SASP may be harnessed therapeutically.

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Overview of the role of neoadjuvant chemotherapy for early stage non[ndash ]small cell lung cancer

Seminars in Oncology ◽

10.1053/sonc.2001.27628 ◽

2001 ◽

Vol 28 (4L) ◽

pp. 29-36

Author(s):

Alain Depierre ◽

Virginie Westeel

Keyword(s):

Lung Cancer ◽

Neoadjuvant Chemotherapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Early Stage ◽

Small Cell ◽

Small Cell Lung

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Do we Need Maintenance Chemotherapy in Advanced NSCLC in the Era of Immune and Targeted Therapy?

Current Cancer Therapy Reviews ◽

10.2174/1573394714666180417160205 ◽

2019 ◽

Vol 15 (1) ◽

pp. 50-55

Author(s):

Ahmed Nagy ◽

Omar Abdel Rahman ◽

Heba Abdullah ◽

Ahmed Negida

Keyword(s):

Lung Cancer ◽

Maintenance Therapy ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Statistical Significance ◽

Small Cell ◽

Maintenance Chemotherapy ◽

Small Cell Lung ◽

The Impact

Background: Although well established for the effective management of hematologic cancers, maintenance chemotherapy has only been recently incorportated as a treatment paradigm for advanced non–small-cell lung cancer. Maintenance chemotherapy aims to prolong a clinically favorable response state achieved after finishing induction therapy which is usually predefined in number before startng treatment. There are 2 modalities for maintenance therapy; continuation maintenance (involving a non-platinum component which was a part of the induction protocol or a targeted agent) and switch maintenance therapy (utilizing a new agent which was not a part of the induction regimen). Methods: The purpose of this article is to review the role of maintenance therapy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC) and provide a brief overview about induction chemotherapy in NSCLC to address the basis of maintenance therapy as a treatment option. We will also compare the impact of maintenance chemotherapy with the now evolving role of immunotherapy in NSCLC. Results: There have been 4 maintenance studies to date showing prolonged PFS and OS with statistical significance. However, Three out of the four studies (ECOG4599, JMEN, and PARAMOUNT) did not report tumor molecular analysis. As regard Immunotherapy, current data is in favour of strongly an increasing role for immunotherapy in NSCLC. Conclusion: Maintenance therapy in NSCLC continues to be an important therapeutic line to improve outcome in patients with metastatic and recurrent disease.

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