scholarly journals The Nutritional Cytokine Leptin Promotes NSCLC by Activating the PI3K/AKT and MAPK/ERK Pathways in NSCLC Cells in a Paracrine Manner

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Fengzhou Li ◽  
Shilei Zhao ◽  
Tao Guo ◽  
Jinxiu Li ◽  
Chundong Gu
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Western Blot ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Serum Leptin ◽  
Coculture System

Purpose.Leptin is a nutritional cytokine encoded by the obesity gene whose concentration in the tumor microenvironment is closely related to the occurrence and progression of cancer. However, previous evidence has suggested that there is no clear relationship between serum leptin concentrations and lung cancer progression. Cancer-associated fibroblasts (CAFs), the most abundant component of the tumor microenvironment in a variety of solid tumors, were recently reported to produce leptin. Therefore, it was inferred that leptin is most likely to affect non-small-cell lung cancer (NSCLC) through an autocrine and paracrine mechanism. In the current study, we investigated the paracrine effect and mechanism of leptin produced by CAFs on NSCLC by establishing a novel in vitro cell coculture system.Methods.A noncontact coculture device was designed and made by 3D printing. CAFs and paired normal lung fibroblasts (NLFs) from 5 patients were successfully isolated and cocultured with two NSCLC cell lines in a coculture system. The background expression of leptin was detected by western blot. The in situ expression of leptin and its receptor (Ob-R) in NSCLC tissues and paired normal lung tissues was analyzed by immunohistochemistry. Furthermore, we downregulated the expression of leptin in CAFs and assessed changes in its promotion on NSCLC cells in the coculture system. Finally, changes in the phosphorylation of ERK1/2 and AKT were examined to investigate the molecular mechanisms responsible for the paracrine promotion of NSCLC cells by leptin.Results.Leptin was overexpressed in nearly all five primary CAF lines compared with its expression in paired NLFs. IHC staining showed that the expression of leptin was high in NSCLC cells, slightly lower in CAF, and negative in normal lung tissue. Ob-R was strongly expressed in NSCLC cells. The ability of A549 and H1299 cells to proliferate and migrate was enhanced by high leptin levels in both the cocultured fibroblasts and the culture medium. Furthermore, western blot assays suggested that the MAPK/ERK1/2 and PI3K/AKT signaling pathways were activated by leptin produced by CAFs, which demonstrated that the functions of paracrine leptin in NSCLC are as those of the serum leptin to other cancers.Conclusion.Leptin produced by CAF promotes proliferation and migration of NSCLC cells probably via PI3K/AKT and MAPK/ERK1/2 signaling pathways in a paracrine manner.

scholarly journals The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment

2014 ◽  
Vol 2014 ◽  
pp. 1-19 ◽  
Author(s):  
Norahayu Othman ◽  
Noor Hasima Nagoor
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
High Frequency ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Lung Carcinogenesis ◽  
The Past ◽  
Late Stage Diagnosis ◽  
Anticancer Treatment

Lung cancer remains to be one of the most common and serious types of cancer worldwide. While treatment is available, the survival rate of this cancer is still critically low due to late stage diagnosis and high frequency of drug resistance, thus highlighting the pressing need for a greater understanding of the molecular mechanisms involved in lung carcinogenesis. Studies in the past years have evidenced that microRNAs (miRNAs) are critical players in the regulation of various biological functions, including apoptosis, which is a process frequently evaded in cancer progression. Recently, miRNAs were demonstrated to possess proapoptotic or antiapoptotic abilities through the targeting of oncogenes or tumor suppressor genes. This review examines the involvement of miRNAs in the apoptotic process of lung cancer and will also touch on the promising evidence supporting the role of miRNAs in regulating sensitivity to anticancer treatment.

scholarly journals Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer

2020 ◽  
Vol 10 (3) ◽  
pp. 109 ◽  
Author(s):  
Hee Sung Chae ◽  
Minchan Gil ◽  
Subbroto Kumar Saha ◽  
Hee Jeung Kwak ◽  
Hwan-Woo Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Prognostic Value ◽  
Mammalian Target Of Rapamycin ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Lung Cancer Cells ◽  
Normal Lung ◽  
Therapeutic Modalities

Lung cancer remains the most dangerous type of cancer despite recent progress in therapeutic modalities. Development of prognostic markers and therapeutic targets is necessary to enhance lung cancer patient survival. Sestrin family genes (Sestrin1, Sestrin2, and Sestrin3) are involved in protecting cells from stress. In particular, Sestrin2, which mainly protects cells from oxidative stress and acts as a leucine sensor protein in mammalian target of rapamycin (mTOR) signaling, is thought to affect various cancers in different ways. To investigate the role of Sestrin2 expression in lung cancer cells, we knocked down Sestrin2 in A549, a non-small cell lung cancer cell line; this resulted in reduced cell proliferation, migration, sphere formation, and drug resistance, suggesting that Sestrin2 is closely related to lung cancer progression. We analyzed Sestrin2 expression in human tissue using various bioinformatic databases and confirmed higher expression of Sestrin2 in lung cancer cells than in normal lung cells using Oncomine and the Human Protein Atlas. Moreover, analyses using Prognoscan and KMplotter showed that Sestrin2 expression is negatively correlated with the survival of lung cancer patients in multiple datasets. Co-expressed gene analysis revealed Sestrin2-regulated genes and possible associated pathways. Overall, these data suggest that Sestrin2 expression has prognostic value and that it is a possible therapeutic target in lung cancer.

scholarly journals Iron as a Central Player and Promising Target in Cancer Progression

2019 ◽  
Vol 20 (2) ◽  
pp. 273 ◽  
Author(s):  
Michaela Jung ◽  
Christina Mertens ◽  
Elisa Tomat ◽  
Bernhard Brüne
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Cancer Progression ◽  
Crucial Role ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Tumor Therapy ◽  
Essential Element ◽  
Major Function ◽  
Iron Pool

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

Long non-coding RNA and Notch regulation in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
pp. 108-122
Author(s):  
Joanna Pancewicz
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Cell Lung Cancer ◽  
Notch Pathway ◽  
Current Data ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cancer Pathogenesis

Non-small cell lung cancer is one of the most commonly diagnosed cancer with a very high mortality rate. Trying to understand the mechanisms underlying the progression of this type of cancer, it is necessary to evaluate the changes occurring at molecular level in cancer cells. Besides the widely studied signaling pathways and genes which are dysregulated in NSCLC, there is a large group of non-coding RNAs involved in cancer pathogenesis. Those RNAs are tissue specific heterogeneous class of RNAs that play many functions in physiological condition in cells, nevertheless current data has shown that lncRNAs are also functional in different types of cancer. Moreover, it has been suggest that lncRNAs are involved in cancer progression by controlling key signaling pathways involved in diverse types of tumors. Notch signaling is one of those pathways, very often deregulated in NSCLC. Therefore in this review I summarized recent outcomes according the importance of lncRNAs in regulation of Notch pathway in the pathogenesis of NSCLC.

Selection of lung cancer-associated scFv antibodies from cultured cells

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22137-e22137
Author(s):  
P. P. Massion ◽  
T. V. Pedchenko ◽  
D. V. Parekh ◽  
R. Mernaugh
Keyword(s):  
Lung Cancer ◽  
Western Blot ◽  
Cell Lines ◽  
Cancer Cell ◽  
High Throughput ◽  
Cancer Cell Lines ◽  
Normal Lung ◽  
Antibody Library ◽  
Lung Cancer Cell ◽  
Cell Lysates

e22137 Background: Lung cancer is the most common cause of cancer-related deaths in the world. There is a critical need for new strategies of early lung cancer detection. The identification of tumor-associated antigens and corresponding antibodies is one approach to discovery of diagnostic biomarkers. We used a large phage-displayed recombinant antibody library and normal human lung epithelial and non-small cell lung cancer cell lines to select for and identify recombinant antibodies specific for proteins expressed, or over-expressed, in lung cancer. Methods: The antibody library was used to select for recombinant scFv antibodies reactive with proteins present, or aberrantly expressed, in non-small cell lung cancer cell lines (A549, H549, H157, H23) in comparison to normal lung cell lines (BEAS-2B, 16-HBE, KT). Soluble scFv antibodies were obtained through 2 rounds of phage antibody cross-absorption (on normal cell lines) and selection (on non-small lung cancer cell lines). Soluble scFv were assayed by a high-throughput fluorometric microvolume assay technology (FMAT) against normal and cancer lung cell line proteins. ScFv antibodies selected by FMAT were evaluated further with Western blot-based assays. Results: More than 100 scFv antibodies identified by FMAT bound preferentially to proteins in lung cancer. Of these, 46 scFv were assayed by a high throughput Western slot blot immunoassay against pooled normal lung and lung cancer cell lysates. Eight scFv were assayed in Western blot against individual lung normal and non-small lung cancer cell line lysates. Four of these demonstrated differential binding to normal and cancer cell lysates. Conclusions: In summary, we were able to detect cancer-associated antigens in lung cancer cell lines using a phage display antibody library. In combination with high-throughput fluorescent and Western blot assays, four unique scFv antibodies were selected that differentially bound to normal and lung cancer cell lysates. These scFv will be tested as candidate biomarkers of lung cancer in independent tissue and serum samples from patient with and without lung cancer to determine utility for use in lung cancer diagnosis. No significant financial relationships to disclose.

scholarly journals Extracellular HSP90 Machineries Build Tumor Microenvironment and Boost Cancer Progression

2021 ◽  
Vol 9 ◽  
Author(s):  
Pietro Poggio ◽  
Matteo Sorge ◽  
Laura Seclì ◽  
Mara Brancaccio
Keyword(s):  
Tumor Microenvironment ◽  
Cell Surface ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Diagnostic Tools ◽  
Surface Receptors ◽  
And Behavior ◽  
Cancer Cell Signaling ◽  
The Impact ◽  
Stimulation Of

HSP90 is released by cancer cells in the tumor microenvironment where it associates with different co-chaperones generating complexes with specific functions, ranging from folding and activation of extracellular clients to the stimulation of cell surface receptors. Emerging data indicate that these functions are essential for tumor growth and progression. The understanding of the exact composition of extracellular HSP90 complexes and the molecular mechanisms at the basis of their functions in the tumor microenvironment may represent the first step to design innovative diagnostic tools and new effective therapies. Here we review the impact of extracellular HSP90 complexes on cancer cell signaling and behavior.

scholarly journals Sulforaphane Inhibits Self-renewal of Lung Cancer Stem Cells Through the Modulation of Polyhomeotic Homolog 3 and Sonic Hedgehog Signaling Pathways

2019 ◽  
Author(s):  
FanPing Wang ◽  
Jiateng Zhong ◽  
Shanshan Wang ◽  
Caijuan Qiao ◽  
Xiangyang Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Western Blot ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Sonic Hedgehog ◽  
Self Renewal ◽  
Shh Signaling ◽  
Lung Cancer Stem Cells

Abstract Background: Sulforaphane (SFN), an active compound in cruciferous vegetables has been characterized for its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. Methods: Lung cancer stem cells (CD133-positive cells) were isolated by MACs and then measured by flow cytometry. The ability of cell proliferation was assessed by MTT assays and tumorsphere formation assays. The expressions of Sonic Hedgehog (Shh), Smoothened (Smo), Gli1 and Human Polyhomeotic Homolog 3 (PHC3) in cells were measured by quantitative reverse transcription polymerase chain reaction (qPCR) and western blot assays. The expression of transcription factor SOX2 in lung cancer stem cells was also determined by western blot assay. Shh was knocked down by siRNA to further study the role of SFN and Shh signaling pathways in lung cancer. Results: SFN inhibited the proliferation of lung cancer cells and lung cancer stem cells simultaneously. Meanwhile, we observed that Sonic Hedgehog (SHH) signaling pathway, SOX2 and Polyhomeotic Homolog 3 (PHC3) were highly activated in lung cancer stem cells. Knock-down of Shh led to reduced H460 and A549 cells proliferation. Furthermore, we observed that SFN inhibited the activity of PHC3 and SHH signaling pathways in the lung cancer stem cells. In addition, SFN combined with Knock-down of Shh gene showed a greater effect on the proliferation of lung cancer cells. Conclusion: SFN is an effective new drug which can inhibit proliferation of lung cancer stem cells through the modulation of PHC3 and SHH signaling pathways. It provides a novel target for improving therapeutic efficacy for lung cancer stem cells.

scholarly journals LncRNA LINC00240 suppresses invasion and migration in non-small cell lung cancer by sponging miR-7-5p

2020 ◽  
Author(s):  
gwan woo Ku ◽  
Yujin Kang ◽  
Seong-Lan Yu ◽  
Joonghoon Park ◽  
Sejin Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Normal Lung ◽  
Lung Cancer Cell ◽  
Invasion And Migration ◽  
And Migration

Abstract Background: lncRNAs have important roles in regulating cancer biology. Accumulating evidence has established a link between the dysregulation of lncRNAs and microRNA in cancer progression. In previous studies, miR-7-5p has been found to be significantly down-regulated in mesenchymal-like lung cancer cell lines and directly regulated EGFR. In this work, we investigated the lncRNA partner of miR-7-5p in the progression of lung cancer.Methods: We investigated the expression of miR-7-5p and the lncRNA after transfection with an miR-7-5p mimics using a microarray. The microarray results were validated using quantitative real time-polymerase Chain Reaction (qRT-PCR). The regulatory effects of lncRNA on miR-7-5p and its target were evaluated by changes in the expression of miR-7-5p after transfection with siRNAs for lncRNA and the synthesis of full-length lncRNA. The effect of miR-7-5p on lncRNA and the miRNA target was evaluated after transfection with miRNA mimic and inhibitor. The role of lncRNA in cancer progression was determined using invasion and migration assays. The level of lncRNA and EGFR in lung cancer and normal lung tissue was analyzed using TCGA data.Results: We found that LINC00240 was downregulated in lung cancer cell line after miR-7-5p transfection with an miR-7-5p mimic. Further investigations revealed that the knockdown of LINC00240 induced the overexpression of miR-7-5p. The overexpression of miR-7-5p diminished cancer invasion and migration. The EGFR expression was down regulated after siRNA treatment for LINC00240. Silencing LINC00240 suppressed the invasion and migration of lung cancer cells, whereas LINC00240 overexpression exerted the opposite effect. The lower expression of LINC00240 in squamous lung cancer was analyzed using TCGA data.Conclusions: Taken together, LINC00240 acted as a sponge for miR-7-5p and induced the overexpression of EGFR. LINC00240 may represent a potential target for the treatment of lung cancer.

scholarly journals Histone methyltransferase SETD1A participates in lung cancer progression

2020 ◽  
Author(s):  
Mei Du ◽  
Piping Gong ◽  
Yun Zhang ◽  
Yanguo Liu ◽  
Xiaozhen Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Normal Lung ◽  
Control Group ◽  
Cancer Tissue ◽  
Mesenchymal Transition ◽  
Cancer Symptoms ◽  
Mechanistic Analysis

Abstract Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

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