Long non-coding RNA MEG3 regulates migration and invasion of lung cancer stem cells via miR-650/SLC34A2 axis

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.

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Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells

Journal of Translational Medicine ◽

10.1186/s12967-021-02902-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Narumol Bhummaphan ◽

Piyapat Pin-on ◽

Preeyaporn Plaimee Phiboonchaiyanan ◽

Jirattha Siriluksana ◽

Chatchawit Aporntewan ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cell ◽

Transcriptional Control ◽

Single Gene ◽

Repeat Sequence ◽

Control Activity ◽

Multiple Genes ◽

Lung Cancer Stem Cells

Abstract Background Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Methods First, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs. Results The number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs. Conclusion PNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.

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The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy

FEBS Open Bio ◽

10.1002/2211-5463.13207 ◽

2021 ◽

Author(s):

Doudou Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

Jingyuan Li ◽

Bin Zeng ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Human Lung ◽

Mitochondrial Fission ◽

Human Lung Cancer ◽

Lung Cancer Stem Cells

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Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Cancers ◽

10.3390/cancers13122996 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2996

Author(s):

Agata Raniszewska ◽

Iwona Kwiecień ◽

Elżbieta Rutkowska ◽

Piotr Rzepecki ◽

Joanna Domagała-Kulawik

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Early Recognition ◽

Human Life ◽

Clonal Evolution ◽

Diagnostic Techniques ◽

Complex Processes ◽

Age Related ◽

Lung Cancer Stem Cells

Lung cancer remains one of the most aggressive solid tumors with an overall poor prognosis. Molecular studies carried out on lung tumors during treatment have shown the phenomenon of clonal evolution, thereby promoting the occurrence of a temporal heterogeneity of the tumor. Therefore, the biology of lung cancer is interesting. Cancer stem cells (CSCs) are involved in tumor initiation and metastasis. Aging is still the most important risk factor for lung cancer development. Spontaneously occurring mutations accumulate in normal stem cells or/and progenitor cells by human life resulting in the formation of CSCs. Deepening knowledge of these complex processes and improving early recognition and markers of predictive value are of utmost importance. In this paper, we discuss the CSC hypothesis with an emphasis on age-related changes that initiate carcinogenesis. We analyze the current literature in the field, describe our own experience in CSC investigation and discuss the technical challenges with special emphasis on liquid biopsy.

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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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Autophagy augments the self-renewal of lung cancer stem cells by the degradation of ubiquitinated p53

Cell Death and Disease ◽

10.1038/s41419-021-03392-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianyu Wang ◽

Doudou Liu ◽

Zhiwei Sun ◽

Ting Ye ◽

Jingyuan Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cell Lines ◽

Human Cancer ◽

Suppressor Activity ◽

Self Renewal ◽

Tumor Suppressor Activity ◽

Lung Cancer Stem Cells ◽

First Time

AbstractIt has been postulated that cancer stem cells (CSCs) are involved in all aspects of human cancer, although the mechanisms governing the regulation of CSC self-renewal in the cancer state remain poorly defined. In the literature, both the pro- and anti-oncogenic activities of autophagy have been demonstrated and are context-dependent. Mounting evidence has shown augmentation of CSC stemness by autophagy, yet mechanistic characterization and understanding are lacking. In the present study, by generating stable human lung CSC cell lines with the wild-type TP53 (A549), as well as cell lines in which TP53 was deleted (H1229), we show, for the first time, that autophagy augments the stemness of lung CSCs by degrading ubiquitinated p53. Furthermore, Zeb1 is required for TP53 regulation of CSC self-renewal. Moreover, TCGA data mining and analysis show that Atg5 and Zeb1 are poor prognostic markers of lung cancer. In summary, this study has elucidated a new CSC-based mechanism underlying the oncogenic activity of autophagy and the tumor suppressor activity of p53 in cancer, i.e., CSCs can exploit the autophagy-p53-Zeb1 axis for self-renewal, oncogenesis, and progression.

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Investigating the Radioresistant Properties of Lung Cancer Stem Cells in the Context of the Tumor Microenvironment

Radiation Research ◽

10.1667/rr14285.1 ◽

2016 ◽

Vol 185 (2) ◽

pp. 169-181 ◽

Cited By ~ 18

Author(s):

Ryan Chan ◽

Pallavi Sethi ◽

Amar Jyoti ◽

Ronald McGarry ◽

Meenakshi Upreti

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Lung Cancer Stem Cells

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Bone Marrow Mesenchymal Stem Cells (BMSCs) Restrain the Malignant Behaviors of A549 Lung Cancer Cells Under Hypoxia via miR-145

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2926 ◽

2022 ◽

Vol 12 (3) ◽

pp. 597-601

Author(s):

Haibin Song ◽

Heng Zhang ◽

Lei Li

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Cancer Stem Cells ◽

Cell Invasion ◽

A549 Cells ◽

Hypoxia Group ◽

Marrow Mesenchymal Stem Cells ◽

Lung Cancer Stem Cells

Deriving from bone marrow, the bone marrow mesenchymal stem cells (BMSCs) possess multipolar chemotaxis, proliferation potential, along with the capability to differentiate into various types of cells. Moreover, the hypoxic stimulation can effectively induce BMSCs differentiation. This study intends to explore the impediment of BMSCs on malignant behaviors of lung cancer stem cells under hypoxia. A co-culture system of BMSCs with A549 cells was established and then assigned into normoxia group, hypoxia group (50, 100, and 200 nmol/L) followed by analysis of cell viability by CCK-8 assay and miR-145 expression by qRT-PCR. In addition, A549 cells were grouped into NC group, miR-145-mimics group, and miR-145-inhibitors group followed by analysis of cell invasion and levels of miR-145 and Oct4. Hypoxia group exhibited a reduced cell viability and higher miR-145 expression (146.01±21.23%) compared to normoxia group (P < 0.05). Transfection of miR-145-mimic significantly upregulated miR-145 and decreased cell invasion (7.49±1.43%) compared with miR-145-inhibitors group or NC group (P < 0.05). Meanwhile, Oct4 level in miR-145-mimics group (0.934±2.98) was significantly decreased (P < 0.05). In conclusion, under hypoxia condition, the co-culture with BMSCs can upregulated miR-145 level, effectively reduce the viability of lung cancer stem cells and restrain proliferation capability.

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