Role of microRNAs in regulating cell proliferation, metastasis and chemoresistance and their applications as cancer biomarkers in small cell lung cancer

We aim to discuss comprehensively the role of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in small-cell lung cancer (SCLC) biology and their clinical utility as cancer biomarkers. We searched the scientific literature to select articles related to the role of lncRNAs and circRNAs in SCLC biology or as cancer biomarkers. We identified that a number of lncRNAs and circRNAs can regulate key biological processes involved in SCLC development, including cell proliferation, metastasis and chemoresistance mainly acting as miRNA sponges. Also, the expression of a few lncRNAs and circRNAs predicted survival outcome depicting their utility as prognostic biomarkers. Further investigations on the role of lncRNAs and circRNAs in SCLC tumors may yield novel therapeutic targets for SCLC.

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Circ_0005962 functions as an oncogene to aggravate non-small cell lung cancer progression via circ_0005962/miR-382-5p/PDK4 regulatory network

10.1101/2020.03.06.980185 ◽

2020 ◽

Author(s):

Zhihong Zhang ◽

Zhenxiu Shan ◽

Rubin Chen ◽

Xiaorong Peng ◽

Bin Xu ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Caspase 3 ◽

Small Cell ◽

Luciferase Reporter ◽

Small Cell Lung

AbstractNon-small cell lung cancer (NSCLC) is a leading threat to human lives with high incidence and mortality. Circular RNAs (circRNAs) were reported to play important roles in human cancers. The purpose of this study was to investigate the role of circ_0005962 and explore the underlying functional mechanisms. The expression of circ_0005962, miR-382-5p and pyruvate dehydrogenase kinase 4 (PDK4) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and cell apoptosis were assessed by cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The protein levels of Beclin 1, light chain3 (LC3-II/LC3-I), PDK4, Cleaved Caspase 3 (C-caspase 3) and proliferating cell nuclear antigen (PCNA) were examined using western blot analysis. Glycolysis was determined according to the levels of glucose consumption and lactate production. The interaction between miR-382-5p and circ_0005962 or PDK4 was predicted by the online tool CircInteractome or starbase and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft model was constructed to investigate the role of circ_0005962 in vivo. circ_0005962 expressed with a high level in NSCLC tissues and cells. Circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but promoted apoptosis in NSCLC cells. MiR-382-5p was targeted by circ_0005962, and its inhibition reversed the role of circ_0005962 knockdown. Besides, PDK4, a target of miR-382-5p, was regulated by circ_0005962 through miR-382-5p, and its overexpression abolished the effects of miR-382-5p reintroduction. Circ_0005962 knockdown suppressed tumor growth in vivo. Circ_0005962 knockdown restrained cell proliferation, autophagy, and glycolysis but stimulated apoptosis through modulating the circ_0005962/miR-382-5p/PDK4 axis. Our study broadened the insights into understanding the mechanism of NSCLC progression.

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KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signaling pathway

Cell Death and Differentiation ◽

10.1038/s41418-020-00651-5 ◽

2020 ◽

Author(s):

Wenwen Du ◽

Jianjie Zhu ◽

Yuanyuan Zeng ◽

Ting Liu ◽

Yang Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Small Cell Lung

Abstract In addition to the role of programmed cell death ligand 1 (PD-L1) in facilitating tumour cells escape from immune surveillance, it is considered as a crucial effector in transducing intrinsic signals to promote tumour development. Our previous study has pointed out that PD-L1 promotes non-small cell lung cancer (NSCLC) cell proliferation, but the mechanism remains elusive. Here we first demonstrated that PD-L1 expression levels were positively correlated with p-MerTK levels in patient samples and NSCLC cell lines. In addition, PD-L1 knockdown led to the reduced phosphorylation level of MerTK in vitro. We next showed that PD-L1 regulated NSCLC cell proliferation via Gas6/MerTK signaling pathway in vitro and in vivo. To investigate the underlying mechanism, we unexpectedly found that PD-L1 translocated into the nucleus of cancer cells which was facilitated through the binding of Karyopherin β1 (KPNB1). Nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, regulated the synthesis of Gas6 mRNA and promoted Gas6 secretion to activate MerTK signaling pathway. Taken together, our results shed light on the novel role of nPD-L1 in NSCLC cell proliferation and reveal a new molecular mechanism underlying nPD-L1-mediated Gas6/MerTK signaling activation. All above findings provide the possible combinational implications for PD-L1 targeted immunotherapy in the clinic.

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Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target

Cancers ◽

10.3390/cancers11111683 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1683 ◽

Cited By ~ 8

Author(s):

Frank Aboubakar Nana ◽

Marie Vanderputten ◽

Sebahat Ocak

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Therapeutic Target ◽

Small Cell ◽

Small Cell Lung

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

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Hsa_circ_0003288 facilitates tumor progression by targeting miR-145 in non–small cell lung cancer cells

Cancer Biomarkers ◽

10.3233/cbm-203198 ◽

2021 ◽

pp. 1-9

Author(s):

Li-Na Pan ◽

Yun-Fang Ma ◽

Jia-An Hu ◽

Zhi-Hong Xu

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Migration And Invasion ◽

Small Cell Lung

Circular RNA (circRNA) has been shown to participate in various tumors, including lung cancer. In the present study, we explored the expression and functional relevance of hsa_circ_0003288 in human non-small cell lung cancer (NSCLC). We verified that hsa_circ_0003288 expression was upregulated in lung cancer tissues and cell lines. Overexpression of hsa_circ_0003288 dramatically promoted lung cancer cell proliferation, colony formation, inhibited apoptosis, and increased cell migration and invasion in vitro. Xenograft experiments showed that hsa_circ_0003288 overexpression accelerated tumor growth in vivo. Mechanistically, hsa_circ_0003288 negatively regulated miR-145 to exert the oncogenic role in lung cancer. Overexpression of miR-145 decreased cell proliferation, induced apoptosis, and suppressed migration and invasion in lung cancer. Additionally, miR-145 co-transfection abolished the oncogenic role of hsa_circ_0003288. Collectively, these findings identified a novel regulatory role of hsa_circ_0003288/miR-145 axis in the progression of NSCLC.

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MiR-376a inhibits non-small cell lung cancer cell progression by regulating Rab1A

10.21203/rs.2.14321/v1 ◽

2019 ◽

Author(s):

Zheng-Hao Cao ◽

Jing-Liang Cheng ◽

Xian-Zhao Zheng ◽

Qing-Qing Lv ◽

Jin-Xin Ma ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Crucial Role ◽

Molecular Mechanisms ◽

Small Cell ◽

Migration And Invasion ◽

Small Cell Lung

Abstract Post transcriptional gene regulation of microRNA-376a (miR-376a) plays a crucial role for tumorigenesis and cancer development. However, the potential role of miR-367a in non-small cell lung cancer (NSCLC) remains unclear. In this study, we investigated the crucial role of miR-376a in NSCLC by analyzing miR-376a expression as well as its target genes. Through overexpression strategies, we uncovered the molecular mechanisms underlying miR-376a-mediated tumorigenesis. Quantitative real-time PCR analysis demonstrated miR-376a levels to be significantly decreased in NSCLC cells compared with non-tumorigenic counterparts. Interestingly, miR-376a overexpression potentially repressed NSCLC cell proliferation, migration, and invasion, but increased apoptosis in A549 cells. Using bioinformatic approaches, we predicted that miR-376a targets Rab1A, and further luciferase fusion assay demonstrated Rab1A was a direct target of miR-376a and miR-376a inhibited cell proliferation by regulating the mRNA and protein levels of Rab1A in NSCLC cells. Overall, our findings uncover the miR-376a could suppress NSCLC cells progression via directly targeting Rab1A.

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SPOCK2 Expression Correlates with Non-Small Cell Lung Cancer Proliferation, Invasion, and Tumorigenesis

10.21203/rs.3.rs-535929/v1 ◽

2021 ◽

Author(s):

Yitong Xu ◽

Lijie Liang ◽

Chaonan Zhu ◽

Chenglong Wang ◽

Jun Jiang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Real Time ◽

Nude Mice ◽

Cell Lung Cancer ◽

Real Time Pcr ◽

Small Cell ◽

Small Cell Lung

Abstract Purpose: Lung cancer is one of the leading causes of death worldwide. Sparc (osteonectin), cwcv, and Kazal-like domains proteoglycan 2 (SPOCK2) play important roles in the development and progression of various types of human cancers. However, the role of SPOCK2 in non-small-cell lung cancer (NSCLC) is unclear. Hence, we aimed to elucidate the role of SPOCK2 in NSCLC. Methods: Real-time PCR and immunohistochemistry were used to study the relationship between SPOCK2 expression and the clinicopathology of NSCLC. SPOCK2 expression was modulated using siRNA (knockdown) or pcmv6-myc-DDK-SPOCK2 (overexpression). The invasion and migration abilities of NSCLC cells were assessed using a Transwell chamber assay, and cell proliferation was studied using the MTT and colony formation assays. Furthermore, axilla and tail vein inoculation using nude mice helped elucidate the function of SPOCK2 in vivo. The expression of related proteins was analyzed using western blotting. SPOCK2 methylation was detected using real-time PCR following the treatment of cells with decitabine. Results: The mRNA and protein levels of SPOCK2 were lower in NSCLC tissues than in adjacent normal lung tissues. SPOCK2 overexpression inhibited cell proliferation, migration, and invasion in A549, H1299 cells, and nude mice. Notch and Erk signaling pathways were inhibited by SPOCK2, whereas the Hippo pathway was activated. SPOCK2 was methylated in NSCLC cell lines. SPOCK2 expression was negatively correlated with NSCLC progression. Conclusion: Taken together, our findings indicate that SPOCK2 methylation may result in its low expression, and the levels of SPOCK2 methylation may be associated with poor prognosis in NSCLC.

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LncRNA PCGEM1 induces proliferation and migration in non-small cell lung cancer cells through modulating the miR-590-3p/SOX11 axis

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01600-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Huanshun Wen ◽

Hongxiang Feng ◽

Qianli Ma ◽

Chaoyang Liang

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Small Cell Lung ◽

Carcinogenic Effect

Abstract Background Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers. As reported, long non-coding RNAs (lncRNAs) induce various biological behaviors in cancers. LncRNA PCGEM1 prostate-specific transcript (PCGEM1) is reported to exert carcinogenic effect on certain cancers. Our research aimed to explore the role of PCGEM1 in NSCLC. Methods We enrolled forty NSCLC patients to explore PCGEM1 expression in clinical NSCLC tissues. Colony formation assay, CCK-8, Transwell assay were conducted to reveal cell proliferation, viability, migration and invasion. Luciferase reporter assay, RNA pull down, and RIP assay were performed to investigate the downstream axis of PCGEM1. Results PCGEM1 was significantly upregulated in NSCLC cells and tissues. Subsequently, in vitro loss-of-function experiments illustrated the carcinogenic role of PCGEM1 in NSCLC through promoting viability, proliferation, migration, and invasion. MiR-590-3p was confirmed to be a downstream gene of PCGEM1. Furthermore, SRY-box transcription factor 11 (SOX11) was verified to be a target of miR-590-3p. Additionally, rescue experiments indicated that miR-590-3p inhibitor or pcDNA3.1/SOX11 rescued the impacts of downregulated PCGEM1 on NSCLC cell proliferation, viability, migration and invasion. Conclusions LncRNA PCGEM1 aggravated proliferative and migrative abilities in NSCLC via the miR-590-3p/SOX11 axis.

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PELP1 expressed in non-small cell lung cancer and promotes tumor cell proliferation, metastasis, and drug resistance through MAPK signaling pathway.

10.21203/rs.3.rs-40995/v2 ◽

2020 ◽

Author(s):

Xingen Wang ◽

Weihua Ying ◽

Li Liang

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Small Cell ◽

Small Cell Lung

Abstract Background Lung cancer is one of the tumors with high morbidity and mortality among males and females worldwide. Proline-, glutamic acid-, and leucine-rich protein 1(PELP1) is an estrogen receptor coactivator and functions as a scaffolding protein. Its oncogenic signaling was involved in the progression of several cancers. However, there is little known about the role of PELP1 in the lung cancer. The aim of this study is to explore the role of PELP1 in non-small cell lung cancer. Methods The expression of PELP1 in microarrays of lung cancer tissue and correlation with clinicopathological parameters were performed. RNA interference technology was used to downregulate PELP1 expression in A549 lung cancer cells and the tumor cell’s ability of proliferation, migration, invasion was detected by Cell Count Kit-8 and trans-well essay. In addition, whole genome exon was analyzed by poly-A RNA-sequencing. Results Results showed that PELP1 is overexpressed in the lung cancer specimens and its expression correlate with histological type, smoking status, and EGFR status but no significant prognostic value. Knockdown of PELP1 inhibited cell proliferation, migration, invasion of lung cancer cells. Furthermore, silencing PELP1 in lung tumor cells promotes the sensitivity of tumor cells to the tyrosine kinase inhibitor Gefitinib. RNA-sequencing and Western-blotting found that 140 genes were up-regulated and 143 genes were down-regulated in PELP1 silenced lung adenocarcinoma cells, which mainly affected the mitogen-activated protein kinase (MAPK) signal pathway, EGFR tyrosine kinase inhibitor resistance, PPAR signaling pathway, Cytosolic DNA-sensing pathway, cytokine-cytokine receptor interaction, drug metabolism, cAMP signaling pathway, RIG-1-like receptor signaling pathway. Conclusions PELP1 plays a key role in non-small cell lung cancer proliferation, progression, and drug resistance. These results suggest that PELP1 could be a potential target for therapeutic intervention for lung cancer.

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PELP1 Expressed in Non-Small Cell Lung Cancer and Promotes Tumor Cell Proliferation, Metastasis, and Drug Resistance Through MAPK Signaling Pathway.

10.21203/rs.3.rs-40995/v1 ◽

2020 ◽

Author(s):

Xingen Wang ◽

Weihua Ying ◽

Li Liang

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Small Cell ◽

Small Cell Lung

Abstract Background Lung cancer is one of the tumors with high morbidity and mortality among males and females worldwide. Proline-, glutamic acid-, and leucine-rich protein 1(PELP1) is an estrogen receptor coactivator and functions as a scaffolding protein. Its oncogenic signaling was involved in the progression of several cancers. However, there is little known about the role of PELP1 in the lung cancer. The aim of this study is to explore the role of PELP1 in non-small cell lung cancer. Methods The expression of PELP1 in microarrays of lung cancer tissue and correlation with clinicopathological parameters were performed. RNA interference technology was used to downregulate PELP1 expression in A549 lung cancer cells and the tumor cell’s ability of proliferation, migration, invasion was detected by Cell Count Kit-8 and trans-well essay. In addition, whole genome exon was analyzed by poly-A RNA-sequencing. Results Results showed that PELP1 is overexpressed in the lung cancer specimens and its expression correlate with histological type, smoking status, and EGFR status but no significant prognostic value. Knockdown of PELP1 inhibited cell proliferation, migration, invasion of lung cancer cells. Furthermore, silencing PELP1 in lung tumor cells promotes the sensitivity of tumor cells to the tyrosine kinase inhibitor Gefitinib. RNA-sequencing and Western-blotting found that 140 genes were up-regulated and 143 genes were down-regulated in PELP1 silenced lung adenocarcinoma cells, which mainly affected the mitogen-activated protein kinase (MAPK) signal pathway, EGFR tyrosine kinase inhibitor resistance, PPAR signaling pathway, Cytosolic DNA-sensing pathway, cytokine-cytokine receptor interaction, drug metabolism, cAMP signaling pathway, RIG-1-like receptor signaling pathway. Conclusions PELP1 plays a key role in non-small cell lung cancer proliferation, progression, and drug resistance. These results suggest that PELP1 could be a potential target for therapeutic intervention for lung cancer.

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