LncRNA SFTA1P mediates positive feedback regulation of the Hippo-YAP/TAZ signaling pathway in non-small cell lung cancer

AbstractLong non-coding RNAs (lncRNAs) regulate numerous biological processes involved in both development and carcinogenesis. Hippo-YAP/TAZ signaling, a critical pathway responsible for organ size control, is often dysregulated in a variety of cancers. However, the nature and function of YAP/TAZ-regulated lncRNAs during tumorigenesis remain largely unexplored. By profiling YAP/TAZ-regulated lncRNAs, we identified SFTA1P as a novel transcriptional target and a positive feedback regulator of YAP/TAZ signaling. Using non-small cell lung cancer (NSCLC) cell lines, we show that SFTA1P is transcriptionally activated by YAP/TAZ in a TEAD-dependent manner. Functionally, knockdown of SFTA1P in NSCLC cell lines inhibited proliferation, induced programmed cell death, and compromised their tumorigenic potential. Mechanistically, SFTA1P knockdown decreased TAZ protein abundance and consequently, the expression of YAP/TAZ transcriptional targets. We provide evidence that this phenomenon could potentially be mediated via its interaction with TAZ mRNA to regulate TAZ translation. Our results reveal SFTA1P as a positive feedback regulator of Hippo-YAP/TAZ signaling, which may serve as the molecular basis for lncRNA-based therapies against YAP/TAZ-driven cancers.

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Chidamide increases the sensitivity of non-small cell lung cancer to crizotinib by decreasing c-MET mRNA methylation

10.1101/2020.03.28.012971 ◽

2020 ◽

Author(s):

Nan Ding ◽

Abin You ◽

Wei Tian ◽

Liankun Gu ◽

Dajun Deng

Keyword(s):

Lung Cancer ◽

Synergistic Effect ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Dependent Manner ◽

Free Medium ◽

Small Cell Lung

ABSTRACTIntroductionCrizotinib is a kinase inhibitor targeting c-MET/ALK/ROS1 used as the first-line chemical for the treatment of non-small cell lung cancer (NSCLC) with ALK mutations. Although c-MET is frequently overexpressed in 35-72% of NSCLC, most NSCLCs are primarily resistant to crizotinib treatment.MethodA set of NSCLC cell lines were used to test the effect of chidamide on the crizotinib sensitivity in vitro and in vivo. Relationships between the synergistic effect of chidamide and c-MET expression and RNA methylation were systemically studied with a battery of molecular biological assays.ResultsWe found for the first time that chidamide could increase the crizotinib sensitivity of a set of ALK mutation-free NSCLC cell lines, especially those with high levels of c-MET expression. Notably, chidamide could not increase the crizotinib sensitivity of NSCLC cells cultured in serum-free medium without hepatocyte growth factor (HGF; a c-MET ligand). In contrast, the addition of HGF into the serum-/HGF-free medium could restore the synergistic effect of chidamide. Moreover, the synergistic effect of chidamide could also be abolished either by treatment with c-MET antibody or siRNA-knockdown of c-MET expression. While cells with low or no c-MET expression were primarily resistant to chidamide-crizotinib cotreatment, enforced c-MET overexpression could increase the sensitivity of these cells to chidamide-crizotinib cotreatment. Furthermore, chidamide could decrease c-MET expression by inhibiting mRNA N6-methyladenosine (m6A) modification through the downregulation of METTL3 and WTAP expression. Chidamide-crizotinib cotreatment significantly suppressed the activity of c-MET downstream molecules.Conclusionchidamide downregulated c-MET expression by decreasing its mRNA m6A methylation, subsequently increasing the crizotinib sensitivity of NSCLC cells in a c-MET-/HGF-dependent manner.GRAPHIC SUMMARY

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The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666190410151945 ◽

2019 ◽

Vol 22 (4) ◽

pp. 238-244 ◽

Cited By ~ 2

Author(s):

Gang Chen ◽

Bo Ye

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Normal Lung ◽

Migration And Invasion ◽

Small Cell Lung ◽

Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

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Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

Cell Death and Disease ◽

10.1038/s41419-021-03804-7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Kaili Long ◽

Lili Gu ◽

Lulu Li ◽

Ziyu Zhang ◽

Enjie Li ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Molecular Compound ◽

Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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Comprehensive analysis of prognostic value and immune infiltration of kindlin family members in non-small cell lung cancer

BMC Medical Genomics ◽

10.1186/s12920-021-00967-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xiaoshan Su ◽

Ning Liu ◽

Weijing Wu ◽

Zhixing Zhu ◽

Yuan Xu ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Prognostic Value ◽

Small Cell ◽

Nsclc Cell ◽

Small Cell Lung ◽

Immune Infiltration

Abstract Background Kindlin Family Members have been reported to be aberrantly expressed in various human cancer types and involved in tumorigenesis, tumor progression, and chemoresistance. However, their roles in non-small cell lung cancer (NSCLC) remain poorly elucidated. Methods We analyzed the prognostic value and immune infiltration of Kindlins in NSCLC through Oncomine, GEPIA, UALCAN, CCLE, Kaplan‑Meier plotter, cBioPortal, TIMER, GeneMANIA, STRING, and DAVID database. Additionally, the mRNA expression levels of Kindlins were verified in 30 paired NSCLC tissues and NSCLC cell lines by real-time PCR. Results The expression level of FERMT1 was remarkably increased in NSCLC tissues and NSCLC cell lines, while FERMT2 and FERMT3 were reduced. Kindlins expressions were associated with individual cancer stages and nodal metastasis. We also found that higher expression level of FERMT1 was obviously correlated with worse overall survival (OS) in patients with NSCLC, while higher FERMT2 was strongly associated with better overall survival (OS) and first progression (FP). Additionally, the expression of FERMT2 and FERMT3 were obviously correlated with the immune infiltration of diverse immune cells. Functional enrichment analysis has shown that Kindlins may be significantly correlated with intracellular signal transduction, ATP binding and the PI3K-Akt signaling pathway in NSCLC. Conclusions The research provides a new perspective on the distinct roles of Kindlins in NSCLC and likely has important implications for future novel biomarkers and therapeutic targets in NSCLC.

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Expression Profiles of microRNAs in Drug-Resistant Non-Small Cell Lung Cancer Cell Lines Using microRNA Sequencing

Cellular Physiology and Biochemistry ◽

10.1159/000495921 ◽

2018 ◽

Vol 51 (6) ◽

pp. 2509-2522 ◽

Cited By ~ 9

Author(s):

Shousen Hu ◽

Yongliang Yuan ◽

Zhizhen Song ◽

Dan Yan ◽

Xiangzhen Kong

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Expression Profiles ◽

Small Cell ◽

Nsclc Cell ◽

Drug Resistant ◽

Small Cell Lung

Background/Aims: Drug resistance remains a main obstacle to the treatment of non- small cell lung cancer (NSCLC). The aim of this study was to identify the expression profiles of microRNAs (miRNAs) in drug-resistant NSCLC cell lines. Methods: The expression profiles of miRNAs in drug-resistant NSCLC cell lines were examined using miRNA sequencing, and the common dysregulated miRNAs in these cell lines were identified and analyzed by bioinformatics methods. Results: A total of 29 upregulated miRNAs and 36 downregulated miRNAs were found in the drug-resistant NSCLC cell lines, of which 26 upregulated and 36 downregulated miRNAs were found to be involved in the Ras signaling pathway. The expression levels, survival analysis, and receiver operating characteristic curve of the dysregulated miRNAs based on The Cancer Genome Atlas database for lung adenocarcinoma showed that hsa-mir-192, hsa-mir-1293, hsa-mir-194, hsa-mir-561, hsa-mir-205, hsa-mir-30a, and hsa-mir-30c were related to lung cancer, whereas only hsa-mir-1293 and hsa-mir-561 were not involved in drug resistance. Conclusion: The results of this study may provide novel biomarkers for drug resistance in NSCLC and potential therapies for overcoming drug resistance, and may also reveal the potential mechanisms underlying drug resistance in this disease.

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Long noncoding RNA HOXA-AS2 promotes non-small cell lung cancer progression by regulating miR-520a-3p

Bioscience Reports ◽

10.1042/bsr20190283 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 3

Author(s):

Yunpeng Liu ◽

Xingyu Lin ◽

Shiyao Zhou ◽

Peng Zhang ◽

Guoguang Shao ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Small Cell Lung

Abstract Background: The HOXA cluster antisense RNA 2 (HOXA-AS2) has recently been discovered to be involved in carcinogenesis in multiple cancers. However, the role and underlying mechanism of HOXA-AS2 in non-small cell lung cancer (NSCLC) yet need to be unraveled. Methods: HOXA-AS2 expression in NSCLC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). Furthermore, the effects of HOXA-AS2 on NSCLC cell proliferation, apoptosis, migration, and invasion were assessed by MTS, flow cytometry, wound healing and transwell invasion assays, respectively. Starbase2.0 predicted and luciferase reporter and RNA immunoprecipitation (RIP) assays were used to validate the association of HOXA-AS2 and miR-520a-3p in NSCLC cells. Results: Our results revealed that HOXA-AS2 in NSCLC tissues were up-regulated and cell lines, and were associated with poor prognosis and overall survival. Further functional assays demonstrated that HOXA-AS2 knockdown significantly inhibited NSCLC cell proliferation, induced cell apoptosis and suppressed migration and invasion. Starbase2.0 predicted that HOXA-AS2 sponge miR-520a-3p at 3′-UTR, which was confirmed using luciferase reporter and RIP assays. miR-520a-3p expression was inversely correlated with HOXA-AS2 expression in NSCLC tissues. In addition, miR-520a-3p inhibitor attenuated the inhibitory effect of HOXD-AS2-depletion on cell proliferation, migration and invasion of NSCLC cells. Moreover, HOXA-AS2 could regulate HOXD8 and MAP3K2 expression, two known targets of miR-520a-3p in NSCLC. Conclusion: These findings implied that HOXA-AS2 promoted NSCLC progression by regulating miR-520a-3p, suggesting that HOXA-AS2 could serve as a therapeutic target for NSCLC.

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