Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway

AimsRadiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms.MethodsNon-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo.ResultsCompared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients.ConclusionsTreatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.

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Long non-coding RNA AFAP1-AS1 accelerates lung cancer cells migration and invasion by interacting with SNIP1 to upregulate c-Myc

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00562-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Yu Zhong ◽

Liting Yang ◽

Fang Xiong ◽

Yi He ◽

Yanyan Tang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Metastasis ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Lung Cancer Patients ◽

Lung Cancer Metastasis ◽

Non Coding Rna ◽

Long Non Coding Rna

AbstractActin filament associated protein 1 antisense RNA 1 (named AFAP1-AS1) is a long non-coding RNA and overexpressed in many cancers. This study aimed to identify the role and mechanism of AFAP1-AS1 in lung cancer. The AFAP1-AS1 expression was firstly assessed in 187 paraffin-embedded lung cancer and 36 normal lung epithelial tissues by in situ hybridization. The migration and invasion abilities of AFAP1-AS1 were investigated in lung cancer cells. To uncover the molecular mechanism about AFAP1-AS1 function in lung cancer, we screened proteins that interact with AFAP1-AS1 by RNA pull down and the mass spectrometry analyses. AFAP1-AS1 was highly expressed in lung cancer clinical tissues and its expression was positively correlated with lung cancer patients’ poor prognosis. In vivo experiments confirmed that AFAP1-AS1 could promote lung cancer metastasis. AFAP1-AS1 promoted lung cancer cells migration and invasion through interacting with Smad nuclear interacting protein 1 (named SNIP1), which inhibited ubiquitination and degradation of c-Myc protein. Upregulation of c-Myc molecule in turn promoted the expression of ZEB1, ZEB2, and SNAIL gene, which ultimately enhanced epithelial to mesenchymal transition (EMT) and lung cancer metastasis. Understanding the molecular mechanism by which AFAP1-AS1 promotes lung cancer’s migration and invasion may provide novel therapeutic targets for lung cancer patients’ early diagnosis and therapy.

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Comprehensive cancer genomics-based screening of new therapeutic targets and biomarkers for lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21031 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21031-e21031

Author(s):

Yataro Daigo ◽

Atsushi Takano ◽

Yusuke Nakamura

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Therapeutic Target ◽

Cancer Genomics ◽

Cancer Biomarkers ◽

Lung Cancer Cells ◽

Lung Cancers ◽

Lung Cancer Patients ◽

Target Molecules

e21031 Background: Since the clinical outcome of advanced lung cancer patients is still poor after standard therapies, development of new anti-cancer drugs with minimum risk of adverse effects and cancer biomarkers for precision medicine is urgently required. Methods: We have been screening new therapeutic target molecules and molecular biomarkers for lung cancers as follows; i) To identify overexpressed genes in lung cancers by the gene expression profile analysis, ii) To verify the target genes for their scarce expression in normal tissues, iii) To validate the clinicopathologic importance of their protein expression by tissue microarray covering 263 lung cancers, and iv) To confirm their function for the growth and/or invasive ability of the lung cancer cells by siRNAs and gene transfection assays. Results: We identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis of lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Conclusions: Comprehensive cancer genomics-based screening could be useful for selection of new cancer biomarkers and molecular targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies.

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Tumor-Intrinsic Response to IFNγ Shapes the Tumor Microenvironment and Anti-PD-1 Response in NSCLC

10.1101/531236 ◽

2019 ◽

Author(s):

Bonnie L. Bullock ◽

Abigail K. Kimball ◽

Joanna M. Poczobutt ◽

Howard Y. Li ◽

Jeff W. Kwak ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Rna Seq ◽

Lung Cancer Cell ◽

Immunocompetent Mouse ◽

Lung Cancer Patients ◽

T Cell Infiltration ◽

Basal Expression

AbstractTargeting PD-1/ PD-L1 is only effective in ~20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated while LLC tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA-Seq analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was absent in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of Socs1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped TME, characterized by enhanced T cell infiltration and enrichment of PD-L1 high myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce of cascade of changes associated with increased therapeutic vulnerability.SummaryMechanisms regulating response to anti-PD-1 therapy in lung cancer are not well defined. This study, using orthotopic immunocompetent mouse models of lung cancer, demonstrates that intrinsic sensitivity of cancer cells to IFNγ determines anti-PD-1 responsiveness through alterations in the tumor microenvironment.

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S100A2 induces the growth of Calu-6 Lung Cancer Cells via apoptosis inhibition, invasion enhancement and promoting cell division

10.21203/rs.2.17525/v1 ◽

2019 ◽

Author(s):

Ting Wang ◽

Yiqian Liang ◽

Asmitananda Thakur

Keyword(s):

Lung Cancer ◽

Cell Division ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Cell Line ◽

Lung Cancer Cell Line ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Apoptosis Inhibition

Abstract Background S100 calcium binding protein A2 (S100A2) has been confirmed to have an abnormal expression in lung cancer and is associated with a better disease-free internal of lung cancer patients. Our previous studies on S100A2 in lung cancer concentrated on the clinical roles of this protein in lung cancer, finding that S100A2 increasingly expressed in the sera, tissues and plural effusion of lung cancer patients. This study emphasizes its value in the lung cancer cell line.Methods We constructed a S100A2 expression lentivirus vector, then transfected it and blank vector into the Calu-6 lung cancer cell line respectively. After the successful transfection, (which was confirmed by RT-PCR and Western-blot), we used MTT, transwell and flow cytometric analysis to compare the differences in cell proliferation, cell migration, cell invasion, cell apoptosis and cell cycle among the three groups (Calu-6, Calu/neo, Calu-6/S100A2).Results Calu-6 lung cancer cells showed a shift from G1 to S phase after being transfected with S100A2, compared with the control groups. Additionally, Calu-6/S1000A2 cells had enhanced abilities of invasion and down-abilities of apoptosis in contrast with the blank groups (P<0.05). However, there were no significant difference among these three group in the cell behaviors of migration and proliferation (P>0.05).Conclusion Our results firstly indicate that S100A2 has a positive influence on the biological characteristics of Calu-6 lung cancer cell line, including cell division, invasion and apoptosis inhibition. It may play a significant role in the genesis and progression of lung cancer.

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Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair

Acta Pharmacologica Sinica ◽

10.1038/aps.2017.187 ◽

2018 ◽

Vol 39 (8) ◽

pp. 1359-1372 ◽

Cited By ~ 5

Author(s):

Xiao-qin Li ◽

Jin Ren ◽

Ping Chen ◽

Yu-jiao Chen ◽

Min Wu ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Dna Damage Repair ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Damage Repair

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Long noncoding RNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 to predict poor prognosis in lung cancer patients

10.21203/rs.2.16166/v2 ◽

2020 ◽

Author(s):

Haihua Tian ◽

Jinchang Pan ◽

Shuai Fang ◽

Chengwei Zhou ◽

Hui Tian ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Western Blot ◽

Cancer Cells ◽

Cancer Patients ◽

Colony Formation ◽

Poor Prognosis ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Cancer Tissues

Abstract Background: Long noncoding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. However, the epigenetic modification of lncRNA and its cognate sense gene in lung cancer remain largely unknown.Methods: qRT-PCR and Western blot were conducted to detect the expressions of DDP10-AS1 and DPP10 expression in lung cancer cell lines and tissues. The impact of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry and xenograft animal experiment. Results: A novel antisense lncRNA, DPP10-AS1, is found to be highly expressed in cancer tissues and the upregulation of DPP10-AS1 predicts poor prognosis in lung cancer patients. Notably, DPP10-AS1 promotes lung cancer cell growth, colony formation, cell cycle progression and represses apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitates lung tumor growth via upregulation of DPP10 protein in xenograft mouse model. Importantly, DPP10-AS1 positively regulates DPP10 gene expression and they are coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 associates with DPP10 mRNA but does not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributes to their coordinate upregulation in lung cancer.Conclusions: These findings indicate that the upregulated antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10, and DPP10-AS1 may act as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

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Long noncoding RNA DPP10-AS1 promotes malignant processes through epigenetically activating its cognate gene DPP10 to predict poor prognosis in lung cancer patients

10.21203/rs.2.16166/v1 ◽

2019 ◽

Author(s):

Haihua Tian ◽

Jinchang Pan ◽

Shuai Fang ◽

Chengwei Zhou ◽

Hui Tian ◽

...

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Western Blot ◽

Cancer Cells ◽

Cancer Patients ◽

Colony Formation ◽

Poor Prognosis ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Cancer Tissues

Abstract Background Long noncoding RNAs (lncRNAs) play oncogenic or tumor-suppressive roles in various cancers. However, the epigenetic modification of lncRNA and its cognate sense gene in lung cancer remain largely unknown.Methods : qRT-PCR and Western blot were conducted to detect the expressions of DDP10-AS1 and DPP10 expression in lung cancer cell lines and tissues. The impact of DDP10-AS1 on DPP10 expression, cell growth, invasion, apoptosis and in vivo tumor growth were investigated in lung cancer cells by Western blot, rescue experiments, colony formation, flow cytometry and xenograft animal experiment.Results A novel antisense lncRNA, DPP10-AS1, is found to be highly expressed in cancer tissues and the upregulation of DPP10-AS1 predicts poor prognosis in lung cancer patients. Notably, DPP10-AS1 promotes lung cancer cell growth, colony formation, cell cycle progression and represses apoptosis in lung cancer cells by upregulating DPP10 expression. Additionally, DPP10-AS1 facilitates lung tumor growth via upregulation of DPP10 protein in xenograft mouse model. Importantly, DPP10-AS1 positively regulates DPP10 gene expression and they are coordinately upregulated in lung cancer tissues. Mechanically, DPP10-AS1 associates with DPP10 mRNA but does not enhance DPP10 mRNA stability. Hypomethylation of DPP10-AS1 and DPP10 contributes to their coordinate upregulation in lung cancer.Conclusions These findings indicate that the upregulated antisense lncRNA DPP10-AS1 promotes lung cancer malignant processes and facilitates tumorigenesis by epigenetically regulating its cognate sense gene DPP10, and DPP10-AS1 may act as a candidate prognostic biomarker and a potential therapeutic target in lung cancer.

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