scholarly journals Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrián Sánchez-Fdez ◽  
María Florencia Re-Louhau ◽  
Pablo Rodríguez-Núñez ◽  
Dolores Ludeña ◽  
Sofía Matilla-Almazán ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Tumor ◽  
Clinical Genetic ◽  
Dismal Prognosis ◽  
Pathophysiological Role ◽  
Inhibition Of Tumor Growth ◽  
Patient Prognosis ◽  
Lung Adenocarcinomas

AbstractDespite advances in its treatment, lung cancer still represents the most common and lethal tumor. Because of that, efforts to decipher the pathophysiological actors that may promote lung tumor generation/progression are being made, with the final aim of establishing new therapeutic options. Using a transgenic mouse model, we formerly demonstrated that the sole activation of the MEK5/ERK5 MAPK route had a pathophysiological role in the onset of lung adenocarcinomas. Given the prevalence of that disease and its frequent dismal prognosis, our findings opened the possibility of targeting the MEK5/ERK5 route with therapeutic purposes. Here we have explored such possibility. We found that increased levels of MEK5/ERK5 correlated with poor patient prognosis in lung cancer. Moreover, using genetic as well as pharmacological tools, we show that targeting the MEK5/ERK5 route is therapeutically effective in lung cancer. Not only genetic disruption of ERK5 by CRISPR/Cas9 caused a relevant inhibition of tumor growth in vitro and in vivo; such ERK5 deficit augmented the antitumoral effect of agents normally used in the lung cancer clinic. The clinical correlation studies together with the pharmacological and genetic results establish the basis for considering the targeting of the MEK5/ERK5 route in the therapy for lung cancer.

scholarly journals Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 208
Author(s):  
David Brunn ◽  
Kati Turkowski ◽  
Stefan Günther ◽  
Andreas Weigert ◽  
Thomas Muley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Lung Tumor ◽  
Interferon Regulatory Factor ◽  
Human Lung Cancer ◽  
Regulatory Factor ◽  
And Migration ◽  
Proliferation And Migration

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.

scholarly journals Construction of Lung Tumor Model for Drug Screening Based on 3D Bio-Printing Technology

2021 ◽  
Vol 11 (7) ◽  
pp. 1213-1226
Author(s):  
Yadong Yang ◽  
Geng Yang ◽  
Xingzhu Liu ◽  
Yimeng Xu ◽  
Siyu Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
3D Model ◽  
Cultured Cells ◽  
Lung Tumor ◽  
Three Dimensional ◽  
Tumor Model ◽  
Traditional Chinese Medicines ◽  
Chinese Medicines

As is known to all, the biological characteristics of two-dimensional (2D) cultured cells are quite different from those in vivo, so the 2D screening model can no longer meet people’s needs. With the development of tissue engineering, people are committed to developing 3D tissue models that can better reflect the biology in vivo, and tend to be mass and miniaturized. In this study, three-dimensional (3D) bio-printing was used to develop an appropriate 3D model for screening sensitive anti-lung cancer drugs in vitro. A549 lung cancer cells were mixed with 8% sodium alginate and 5% gelatin as bio-printing ink to fabricate a cell-laden hydrogel grid scaffold structure. The sensitivity of the printed 3D model to drugs was evaluated with eight anti-tumor traditional Chinese medicines. A fluorescent live/dead staining was carried out at different time to assess the cell survival rate in the 3D scaffolds. MTT assay was used to determine the inhibitory rate of eight antitumor traditional Chinese medicines on A549 cell proliferation in 3D-printed lung tumor models and conventional 2D culture models.

scholarly journals A Non-Coding RNA Landscape of Bronchial Epitheliums of Lung Cancer Patients

Biomedicines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 88
Author(s):  
Yanli Lin ◽  
Van Holden ◽  
Pushpawallie Dhilipkannah ◽  
Janaki Deepak ◽  
Nevins W. Todd ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Lung Tumor ◽  
Pcr Analysis ◽  
Lung Cancer Patients ◽  
Non Coding Rna ◽  
Tumor Tissues ◽  
Nucleolar Rnas

We propose to systematically identify a non-coding RNA (ncRNA) profile of exfoliated bronchial epitheliums of sputum from lung cancer patients. Bronchial epithelial cells enriched from sputum of 32 lung cancer patients and 33 cancer-free smokers were analyzed by next-generation sequencing to comprehensively characterize the ncRNA profiles. In addition, 108 miRNAs, 88 small nucleolar RNAs, 13 piwi-interacting RNAs, 6 transfer RNAs, 4 ribosomal RNAs, 19 small nuclear RNAs, and 25 long-noncoding (lnc) RNAs displayed a significantly different level in bronchial epitheliums of sputum of lung cancer patients versus cancer-free smokers (all <0.001). PCR analysis confirmed their different expression levels in the sputum specimens. A high expression of SNHG9, an lncRNA, was validated in 78 lung tumor tissues, and the expression was inversely associated with overall survival of lung cancer patients (p = 0.002). Knockdown of SNHG9 in cancer cells reduced the cell growth, proliferation, and invasion in vitro and tumorigenesis in vivo. The multiple differentially expressed ncRNAs in bronchial epitheliums may contribute to the development and progression of lung cancer and provide potential biomarkers and therapeutic targets for the disease.

scholarly journals PRMT5 Inhibition Promotes PD-L1 Expression and Immuno-Resistance in Lung Cancer

2022 ◽  
Vol 12 ◽  
Author(s):  
Rui Hu ◽  
Bingqian Zhou ◽  
Zheyi Chen ◽  
Shiyu Chen ◽  
Ningdai Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Tumor Cell ◽  
Lung Tumor ◽  
Inhibitory Effect ◽  
Immunocompetent Mice ◽  
Immunocompromised Mice ◽  
Cell Expression

Protein arginine transferase 5 (PRMT5) has been implicated as an important modulator of tumorigenesis as it promotes tumor cell proliferation, invasion, and metastasis. Studies have largely focused on PRMT5 regulating intrinsic changes in tumors; however, the effects of PRMT5 on the tumor microenvironment and particularly immune cells are largely unknown. Here we found that targeting PRMT5 by genetic or pharmacological inhibition reduced lung tumor progression in immunocompromised mice; however, the effects were weakened in immunocompetent mice. PRMT5 inhibition not only decreased tumor cell survival but also increased the tumor cell expression of CD274 in vitro and in vivo, which activated the PD1/PD-L1 axis and eliminated CD8+T cell antitumor immunity. Mechanistically, PRMT5 regulated CD274 gene expression through symmetric dimethylation of histone H4R3, increased deposition of H3R4me2s on CD274 promoter loci, and inhibition of CD274 gene expression. Targeting PRMT5 reduced this inhibitory effect and promoted CD274 expression in lung cancer. However, PRMT5 inhibitors represent a double-edged sword as they may selectively kill cancer cells but may also disrupt the antitumor immune response. The combination of PRMT5 inhibition and ani-PD-L1 therapy resulted in an increase in the number and enhanced the function of tumor-infiltrating T cells. Our findings address an unmet clinical need in which combining PRMT5 inhibition with anti-PD-L1 therapy could be a promising strategy for lung cancer treatment.

scholarly journals Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH

2018 ◽  
Vol 115 (47) ◽  
pp. 12028-12033 ◽  
Author(s):  
Andrew V. Schally ◽  
Haibo Wang ◽  
Jinlin He ◽  
Renzhi Cai ◽  
Wei Sha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Hormone ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Growth Hormone Releasing Hormone ◽  
Down Regulation ◽  
Releasing Hormone ◽  
Inhibition Of Tumor Growth

The effects of the growth hormone-releasing hormone (GHRH) agonist MR409 on various human cancer cells were investigated. In H446 small cell lung cancer (SCLC) and HCC827 and H460 (non-SCLC) cells, MR409 promoted cell viability, reduced cell apoptosis, and induced the production of cellular cAMP in vitro. Western blot analyses showed that treatment of cancer cells with MR409 up-regulated the expression of cyclins D1 and D2 and cyclin-dependent kinases 4 and 6, down-regulated p27kip1, and significantly increased the expression of the pituitary-type GHRH receptor (pGHRH-R) and its splice-variant (SV1). Hence, in vitro MR409 exerts agonistic action on lung cancer cells in contrast to GHRH antagonists. However, in vivo, MR409 inhibited growth of lung cancers xenografted into nude mice. MR409 given s.c. at 5 μg/day for 4 to 8 weeks significantly suppressed growth of HCC827, H460, and H446 tumors by 48.2%, 48.7%, and 65.6%, respectively. This inhibition of tumor growth by MR409 was accompanied by the down-regulation of the expression of pGHRH-R and SV1 in the pituitary gland and tumors. Tumor inhibitory effects of MR409 in vivo were also observed in other human cancers, including gastric, pancreatic, urothelial, prostatic, mammary, and colorectal. This inhibition of tumor growth parallel to the down-regulation of GHRH-Rs is similar and comparable to the suppression of sex hormone-dependent cancers after the down-regulation of receptors for luteinizing hormone-releasing hormone (LHRH) by LHRH agonists. Further oncological investigations with GHRH agonists are needed to elucidate the underlying mechanisms.

scholarly journals The Role and Molecular Mechanism of SLC34A2 in Stemness Maintenance of CD44+CD166+ Lung Cancer Stem Cells (LCSCs) with AT-II cells’ characteristics

2021 ◽  
Author(s):  
Yan Yang ◽  
Qiang Pu ◽  
Hu Liao ◽  
Yue Yuan ◽  
Xueting Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Malignant Transformation ◽  
Lung Tumor ◽  
Alveolar Epithelium ◽  
Migration And Invasion ◽  
Lung Cancer Stem Cells

Abstract Background Evidence showed some non-small cell lung cancers (NSCLCs) had the type II alveolar epithelium cells’(AT-II cells) characteristics, and AT-II cells were a kind of original stem cells of NSCLCs. But how AT-II cells malignantly transformed into NSCLCs was unclear. Recent evidence indicated SLC34A2 was critical in the development of AT-II cells, and SLC34A2 might be a new gene in the initiation of NSCLCs. However, whether SLC34A2 participated in the malignant transformation of AT-II cells remained unknown. The exact role and mechanism of SLC34A2 in the initiation of NSCLCs needed to be further investigated. Methods The expression of Napi-IIb (encoded by SLC34A2) in the NSCLC cells was compared with that in AT-II cells using immunohistochemistry (IHC). Also coexpression of CD44 and CD166 was detected in these NSCLCs tissues by IHC. Then the CD44+CD166+ cells were sorted from lung tumor spheres by FACS. They were assessed by sphere, proliferation and tumorgenicity assay. Besides, their expression of surfactants C(SP-C) was stained by IHC. Next, the role and mechanism of SLC34A2 in CD44+CD166+ lung cancer stem cells were explored by siRNA-mediated SLC34A2 knockdown, related pathway pharmacological inhibition or activation. In vitro findings were furtherly validated in vivo and NSCLCs samples. Results The expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells in clinic samples. Then the CD44+CD166+ population was identified as CD44+CD166+ lung cancer stem cells (LCSCs). And LCSCs showed abundant expression of SP-C, the hallmark of AT-II cells. Higher expression of SLC34A2 was found in LCSCs compared to their origin NSCLC cells. Additionally, the expression of SLC34A2 was decreased after LCSCs were differentiated, and the morphology of the differentiated cells from LCSCs was similar to their origin NSCLC cells. Knockdown SLC34A2 made declined abilities of self-renewal, drug-resistance, migration and invasion in vitro as well as tumorigenicity in vivo in LCSCs. And SLC34A2 could maintain stemness of LCSCs via PI3K/AKT/STAT3/Sox2 axis. Besides, the connection between SLC34A2 maintaining stemness of lung cancer stem cells and PI3K/AKT/STAT3/Sox2 axis was also validated in vivo and in clinic samples. Conclusions For the first time, we illustrated the expression of SLC34A2 was downregulated in NSCLCs cells compared with AT-II cells. We discovered the downregulated expression of SLC34A2 performed a vital role in the malignant transformation of AT-II cells into NSCLCs. And SLC34A2 could maintain stemness of CD44+CD166+ lung cancer stem cells, which were with AT-II cell’s characteristic, via PI3K/AKT/STAT3/Sox2 axis. It had important significance in the revelation of a new mechanism for the initiation of NSCLCs.

scholarly journals LncRNA DANCR Promotes Lung Cancer by Sequestering miR-216a

2018 ◽  
Vol 25 (1) ◽  
pp. 107327481876984 ◽  
Author(s):  
Qiang Zhen ◽  
Li-na Gao ◽  
Ren-feng Wang ◽  
Wei-wei Chu ◽  
Ya-xiao Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Colony Formation ◽  
Noncoding Rna ◽  
Lung Tumor ◽  
Tumor Xenografts ◽  
Opposing Effects

Background: Long noncoding RNAs (lncRNAs) are a new class of cancer regulators. Here, we aimed to investigate the diagnostic and therapeutic values of an lncRNA, differentiation antagonizing noncoding RNA (DANCR), in lung cancer. Methods: Real-time polymerase chain reaction was used to compare DANCR levels in normal and cancerous lung tissues as well as lung cancer cells. Lentiviral transduction was used to induce DANCR overexpression or silencing in vitro, followed by monitoring cell proliferation, colony formation, and changes in microRNA-216a (miR-216a) expression. DANCR-specific small hairpin RNA transduction was used to establish cells with stable DANCR knockdown, and silenced cells were used to initiate lung tumor xenografts, followed by monitoring tumor growth. Results: DANCR upregulation was seen in lung cancer, particularly in high-grade lung cancer tissues and aggressive cancer cells. Ectopic DANCR expression induced lung cancer cell proliferation and colony formation, whereas DANCR silencing induced opposing effects. The miR-216a level in cancer cells was negatively correlated with DANCR expression. The DANCR knockdown reduced the growth of tumor xenografts in vivo. Conclusion: DANCR upregulation is a potential indicator of aggressive lung cancer. Silencing of DANCR has great potential as a potent therapeutic strategy in lung cancer.

scholarly journals USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription

2021 ◽  
Author(s):  
Xiaohua Jie ◽  
William Pat Fong ◽  
Rui Zhou ◽  
Ye Zhao ◽  
Yingchao Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Affinity Purification ◽  
Smad Signaling ◽  
Lung Cancer Patients ◽  
Lysine Specific Demethylase ◽  
Underlying Mechanisms ◽  
H3k9me3 Level ◽  
Critical Binding

AbstractRadioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 level at the TGF-β2 promoter and then activates Smad/ATM/Chk2 signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner that deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β2/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

scholarly journals MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yipengchen Yin ◽  
Yongjing Li ◽  
Sheng Wang ◽  
Ziliang Dong ◽  
Chao Liang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Membranes ◽  
Imaging System ◽  
Fluorescence Signal ◽  
Bimodal Imaging ◽  
Red Blood Cell Membranes ◽  
Magnetic Resonance Imaging Mri ◽  
Tumor Accumulation

Abstract Background The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as “self”, evade the surveillance of the immune system, and accumulate to the tumor sites actively. Results Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate—an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. Conclusions These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

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