Potential Of Lung Cancer Cells Research Articles

Reprogramming of fibroblasts into cancer-associated fibroblasts via IGF2-mediated autophagy promotes metastasis potential of lung cancer cells

Reprogramming of fibroblasts into cancer-associated fibroblasts via IGF2-mediated autophagy promotes metastasis potential of lung cancer cells

Synthesis and Characterization of Thymoquinone‐Oxime (TQ‐Ox) from Thymoquinone and Evaluation of its Cytotoxic, Genotoxic, and Apoptotic Potential in Lung Cancer Cells (A549) in vitro

AbstractIntro: Thymoquinone(TQ), a compound derived from Nigella sativa, has been found to impede cancer progression, including proliferation, migration, and invasion. Previous research has explored the potential benefits of augmenting TQ with functional groups to enhance its activity, particularly when combined with traditional drugs. The aim of our study was to investigate the therapeutic effects of Thymoquinone‐Oxime(TQ−Ox) on lung cancer cell lines. Methods: To determine the structure of the novel TQ−Ox substance, we employed NMR spectroscopy. We also performed in vitro assays to assess the anti‐cancer mechanisms of TQ−Ox on lung cancer cells(A549) and healthy lung cells(BEAS‐2B). These assays included assessments of cytotoxicity, genotoxicity, and apoptosis, as well as measurements of intracellular Reactive Oxygen Species(iROS), intracellular Calcium(iCa2+), and Mitochondrial Membrane Potential(MMP). Results: Our results demonstrate that TQ−Ox induces dose‐dependent cytotoxicity, genotoxicity, and apoptosis in cancer cells, along with an increase in iROS production. The IC50 values for A549 and BEAS‐2B cells were 41.01 μM and 48.71 μM, respectively. We also observed that as iCa2+ levels increased, there was a decrease in MMP levels(p<0.001). Conclusion: TQ−Ox shows potential as a therapeutic option for lung cancer, justifying further in vitro and in vivo research to explore its clinical applications.

Tumor associated neutrophils governs tumor progression through an IL-10/STAT3/PD-L1 feedback signaling loop in lung cancer

Tumor-associated neutrophils (TANs) can exist in either a pro-inflammatory or an anti-inflammatory state, known as N1 and N2, respectively. Anti-inflammatory TANs have been shown to correlate with poor prognosis and tumor progression in patients. To explore the role and mechanisms of TANs in lung cancer development, we isolated neutrophils from both peripheral blood and tumor tissues of patients/mice, and assessed their functional interaction with lung cancer cells both in vitro and in vivo. Our results revealed that tumor-derived neutrophils (or TANs) promote the tumorigenic and metastatic potential of lung cancer cells. Upon tumorigenesis, TANs display a N2-like status and secrete the cytokine IL-10 to facilitate the activation of c-Met/STAT3 signaling, which ultimately enhances distant metastasis in vivo. Meanwhile, the transcription factor STAT3 increases PD-L1 level in tumor cells, which promotes neutrophils polarization towards a N2-like status, leading to a positive feedback loop between TANs, IL-10, STAT3, PD-L1, and TANs themselves. Blocking IL-10, we additionally eliminated metastatic tumor nodules and enhanced the anticancer effects of chemotherapy in a Lewis mouse model. Our findings suggest a positive feedback loop between tumor cells and TANs that controls tumor progression and patient outcome in lung cancer.

Metformin prevents osteoblast-like potential and calcification in lung cancer A549 cells.

In spite of recent advances made in understanding its progression, cancer is still a leading cause of death across the nations. Molecular pathophysiology of these cancer cells largely differs depending on cancer types and even within the same tumor. Pathological mineralization/calcification is seen in various tissues including breast, prostate, and lung cancer. Osteoblast-like cells derived after trans-differentiation of mesenchymal cells usually drive calcium deposition in various tissues. This study aims to explore the presence of osteoblast-like potential in lung cancer cells and its prevention. ALP assay, ALP staining, nodule formation, RT-PCR, RT-qPCR, and western blot analysis experiments were carried out in lung cancer A549 cells to achieve said objective. Expressions of various osteoblast markers (e.g., ALP, OPN, RUNX2, and Osterix) along with osteoinducer genes (BMP-2 and BMP-4) were observed in A549 cells. Moreover, ALP activity and ability leading to nodule formation revealed the presence of osteoblast-like potential in lung cancer cells. Here, BMP-2 treatment increased expressions of osteoblast transcription factors such as RUNX2 and Osterix, enhanced ALP activity, and augmented calcification in this cell line. It was also observed that antidiabetic metformin inhibited BMP-2 mediated increase in osteoblast-like potential and calcification in these cancer cells. The current study noted that metformin blocked BMP-2 mediated increase in epithelial to mesenchymal transition (EMT) in A549 cells. The above findings for the first time unravel that A549 cells possess osteoblast-like potential which drives lung cancer calcification. Metformin might prevent BMP-2 induced osteoblast-like phenotype of the lung cancer cells with concomitant inhibition of EMT to inhibit lung cancer tissue calcification.

Characterization and Biological Studies of the Terpenoids from Ganoderma resinaceum and Serpula similis (Agaricomycetes)

Mycochemical properties and bioactivities of <i>Ganoderma resinaceum</i> and <i>Serpula similis</i> remain unexplored. The present study assessed antioxidant, cytotoxicity, and cell migration abilities of <i>Ganoderma and Serpula</i> extracts, followed by their phytochemical analyses. The MTT assay was conducted to determine the cytotoxicity along with the cell migration studies in human cancer cell lines. The antioxidant profiles were evaluated through DPPH and FRAP assays. Furthermore, LC-MS/MS analysis was performed to elucidate the phytochemicals responsible for anticancer and antioxidant activities. Significant concentration-dependent cytotoxicities of 12.7% and 13.7% were observed against HCT 116 cell lines at 1% and 5% concentrations of the <i>G. resinaceum </i>extract, respectively. Similarly, significant concentration-dependent cytotoxicities of 6.7% and 25.5% were observed at 1% and 5% concentrations of the <i>S. similis </i>extract, respectively. The extracts of <i>G. resinaceum</i> and <i>S. similis</i> both shows better anti-migration potential in lung cancer cells. Both extracts demonstrated good scavenging activity on DPPH and ferric ion free radicals. LC-MS analysis revealed 11 compounds from <i>S. similis</i> and 15 compounds from <i>G. resinaceum</i> fruiting bodies. Compounds such as terpenoids, alkaloids, cytotoxic peptides, and other metabolites were identified as major components in both extracts. These extracts exhibited cytotoxic activity against HCT 116 cancer cells, along with moderate antioxidant activity. This implies that the extracts might be used as bioactive natural sources in the pharmaceutical and food industries.

Anoikis-Associated Lung Cancer Metastasis: Mechanisms and Therapies.

Simple SummaryAnoikis is a programmed cell death process resulting from the loss of interaction between cells and the extracellular matrix. Therefore, it is necessary to overcome anoikis when tumor cells acquire metastatic potential. In lung cancer, the composition of the extracellular matrix, cell adhesion-related membrane proteins, cytoskeletal regulators, and epithelial–mesenchymal transition are involved in the process of anoikis, and the initiation of apoptosis signals is a critical step in anoikis. Inversely, activation of growth signals counteracts anoikis. This review summarizes the regulators of lung cancer-related anoikis and explores potential drug applications targeting anoikis.Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.

The potential of cannabinoids in the treatment of lung cancer

Introduction: Lung cancer is the number-one cause of death due to neoplasms worldwide. The 5-year overall survival rate is only 22%. In advanced stages, the therapeutic options are limited to chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy. Phytocannabinoids, the components of Cannabis sativa, their synthetic derivatives and endogenous cannabinoids have demonstrated anticancer activity in various common cancers - breast, prostate, colorectal and lung cancers, among others. The aim of this review was to assess the potential value of cannabinoids in the treatment of lung cancer.
 State of knowledge: The majority of preclinical studies demonstrates that cannabinoids inhibit lung cancer cell viability both in vitro and in vivo. The main mechanism of anticancer activity is the induction of apoptosis, triggered by activation of CB1, CB2 and TRPV1 receptors or independently via other pathways. Cannabinoids influence the components of the tumour microenvironment - cancer associated fibroblasts, macrophages and lymphokine-activated-killer cells. Cannabinoids alter leukocyte infiltration into anti-cancer proportions, inhibit expression of EGFR and PAI-1 and increase the expression of TIMP-1. As a result they induce cytotoxicity, decrease proliferation, migration and invasive potential of lung cancer cells, suppress angiogenesis and metastasis forming. Patients with advanced lung cancer may also benefit from analgesic, antiemetic and appetite improving properties of cannabinoids.
 Summary: Cannabinoids can be a supplementary agent in systemic anticancer therapeutic regimen in the future. The exact mechanisms of action, specific doses in anticancer treatment, routes of administration and interactions with other anticancer drugs has yet to be determined. Thus the clinical studies on cannabinoids in lung cancer should be performed in the future.

Knockdown of Peroxiredoxin V increased the cytotoxicity of non-thermal plasma-treated culture medium to A549 cells.

Administration of non-thermal plasma therapy via the use of plasma-activated medium (PAM) might be a novel strategy for cancer treatment, as it induces apoptosis by increasing reactive oxygen species (ROS) levels. Peroxiredoxin V (PRDX5) scavenges ROS and reactive nitrogen species and is known to regulate several physiological and pathological reactions. However, its role in lung cancer cells exposed to PAM is unknown. Here, we investigated the effect of PRDX5 in PAM-treated A549 lung cancer cells and determined the mechanism underlying its cytotoxicity. Cell culture medium was treated with low temperature plasma at 16.4 kV for 0, 60, 120, or 180 s to develop PAM. PRDX5 was knocked down in A549 cells via transfection with short hairpin RNA targeting PRDX5. Colony formation and wound healing assays, flow cytometry, fluorescence microscopy, and western blotting were performed to detect the effect of PRDX5 knockdown on PAM-treated A549 cells. PAM showed higher cytotoxicity in lung cancer cells than in control cells, downregulated the mitogen-activated protein kinase signaling pathway, and induced apoptosis. PRDX5 knockdown significantly inhibited cell colony formation and migration, increased ROS accumulation, and reduced mitochondrial membrane potential in lung cancer cells. Hence, PRDX5 knockdown combined with PAM treatment represents an effective option for lung cancer treatment.

Histologic evaluation of dentin bridge formation by pachymic acid and biodentine in human tooth culture model

Histologic evaluation of dentin bridge formation by pachymic acid and biodentine in human tooth culture model

Potential function of oxymatrine as a novel suppressor of epithelial-to-mesenchymal transition in lung tumor cells

AimsTumor cells metastasis as well as proliferation are important factors that can substantially determines the prognosis of cancer. In particular, epithelial–mesenchymal transition (EMT) is key phenomena which can cause tumor cell transition into other organs by promoting the disruption of the cell-cell junctions. Because oxymatrine (OMT) have been reported to attenuate the tumor growth, we investigated whether OMT can down-regulate EMT process in tumor cells. We also focused on transforming growth factor-β (TGF-β)-induced EMT process because EMT process can be significantly induced by this growth factor. Main methodsThe cell viability was measured by MTT and real time cell analysis (RTCA) assay. The expression levels of various proteins involved in the regulation of EMT and Akt/mTOR/PI3K signaling pathway were evaluated by Western blot analysis. mRNA levels of several important EMT markers were analyzed by reverse transcription polymerase chain reaction (RT-PCR). The effects of OMT on the cellular invasion and migration were evaluated by RTCA, wound healing assay, and boyden chamber assays. Key findingsOMT suppressed the expression of both constitutive and TGF-β-induced mesenchymal markers, such as fibronectin, vimentin, MMP-9, MMP-2, N-cadherin, Twist, and Snail, but induced the levels of epithelial markers. Moreover, OMT down-regulated oncogenic PI3K/Akt/mTOR pathways which lead to a significant attenuation of invasive and migratory potential of lung cancer cells. SignificanceOverall, our study established a novel anti-metastatic role of OMT against human lung cancer cells.

Quercetin Inhibits the Epithelial to Mesenchymal Transition through Suppressing Akt Mediated Nuclear Translocation of β-Catenin in Lung Cancer Cell Line

Lung cancer is a first leading cause of cancer related death worldwide. Quercetin (QUE) has chemo-preventive effect against a variety of cancers. However, the molecular mechanism of QUE mediated inhibition of cancer cell migration and epithelial to mesenchymal transition (EMT) is not clear in lung cancer. Therefore, this study investigates the effect of QUE on EMT and metastasis of lung cancer cell line (A549). The MTT assay, scratch wound healing assay, Transwell migration and invasion assay performed to assess the cell viability and migration potential of lung cancer cells after treatment with different concentration of QUE. Further, chemokines gene expression was analyzed by qPCR and EMT markers were analyzed by immunocytochemistry and Western blot. QUE inhibits cell viability in a dose-dependent (10–80 μM) manner both at 24 and 48 h treatment. The Akt/MAPK/β-catenin and EMT marker protein expressions were decreased significantly, whereas TIMP-2 expression was increased upon QUE treatment. QUE inhibits cell migration and invasion of A-549 cells. In addition, Immunocytochemistry result showed that QUE can reduce nuclear translocalisation of β-catenin in A549 cells. Our results suggest that QUE can inhibit the metastatic potential in lung cancer by altering the Akt/MAPK/β-catenin signaling pathway and inhibiting the nuclear translocation of β-catenin.

Silent information regulator 1 suppresses epithelial-to-mesenchymal transition in lung cancer cells via its regulation of mitochondria status

AimsSilent information regulator 1 (SIRT1) is a NAD+-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, cell metabolism, and mitochondrial functions. Given that it acts as both a tumor promoter and suppressor, the complex mechanisms underlying SIRT1 signaling in cancer remain controversial. Epithelial-to-mesenchymal transition (EMT) plays a key role in the progression of carcinogenesis and tumors metastasis. Studies have shown that mitochondrial defects are critical in EMT process, and SIRT1 is found to regulate the generation and energy metabolism of mitochondria. Here, we elucidate a novel mechanism by which SIRT1 affects EMT in lung cancer cells via its regulation on mitochondria. Main methodsSIRT1 signaling was detected in TGF-β1-induced EMT and was found to regulate mitochondria status, including mitochondrial biogenesis-related protein levels as detected by western blotting, mitochondrial structure observed by transmission electron microscopy, and respiratory functions analyzed by a respiration capacity assay. The effects of modulating SIRT1 expression on EMT and migration of lung cancer cells or normal cells were evaluated by in vitro and in vivo models. Key findingsWe found that the regulation of SIRT1 signaling on the biogenesis or functions of mitochondria was critical to EMT. Overexpression of SIRT1 reduced EMT or metastasis potential of lung cancer cells by improving the quantity and quality of mitochondria, whereas silencing SIRT1 promote EMT in cancer cells, even in normal cells by disturbing mitochondria status. SignificanceConsequently, SIRT1 is an attractive therapeutic target for reversing EMT or tumor metastasis.

LINC10536 Attenuates Lung Adenocarcinoma Proliferation and Metastasis

Background: LUAD is a devastating disease with poor patient prognosis. Long non-coding RNAs (lncRNAs) have been implicated to play a critical role in LUAD progression. Methods: Differentially expressed and methylated tumor suppressor lncRNAs were found using TCGA, GSE81089) and E-MTAB-6957 datasets. The potential biological functions of LINC10536 were examined by loss- and gain-of-function models. Potential downstream pathway was validated by quantitative real-time polymerase chain reaction (RT-qPCR). RNA immunoprecipitation (RIP) arrays were employed to validate the binding between LINC10536 and enhancer of zeste homologue 2 (EZH2). Chromatin immunoprecipitation (CHIP) assays were used to demonstrate CDKN1B and E-cadherin as direct targets of EZH2. Results: The landscape of methylation-mediated tumor suppressor lncRNAs for LUAD were identified in this study. Overexpression of LINC10536 suppressed cell proliferation, cell cycle, invasion, migration and EMT of LUAD cells, whereas knockdown of LINC10536 promoted proliferative and metastatic potential of lung cancer cells in vitro and in vivo. As a nuclear lncRNA LINC10536 knockdown enhanced the occupancy capacity of EZH2 and H3K27me3 at the promoter region of CDKN1B and E-cadherin utilizing CHIP-qPCR. EZH2 knockdown partially reverses the malignant phenotype mediated by shLINC10536 in vitro and in vivo. Moreover, DNA methyltransferase inhibitor 5-azacytosine significantly facilitated LINC10536 expression and its biological functions. Interpretation: Our finding suggests LINC10536 might be a promising target for cancer diagnosis and therapy in clinical practice. Fundings: This project is partially supported by the National Natural Science Foundation of China (81772474, 82072563 to LC and 81803023 to YX). Declaration of Interest: The authors declare that they have no conflict of interest.

Tuberculous Fibrosis Enhances Tumorigenic Potential via the NOX4-Autophagy Axis.

Simple SummaryAlthough previous studies have reported coexistence of pulmonary TB and carcinoma, the underlying mechanism of tuberculous fibrosis-induced tumorigenicity remains to be investigated. We previously reported that NOX4 signaling mediates tuberculous pleural fibrosis by activating ERK–ROS–EMT pathways. We were interested in the role of NOX4 in the tumor microenvironment changed by tuberculosis fibrosis. Our results showed that lung cancer cells enhanced the NOX4 expression and invasive potential after exposure to the conditioned medium of heat-killed Mycobacterium tuberculosis stimulated mesothelial cells or tuberculous pleural effusion. NOX4–autophagy signaling axis contributes to the interaction between tuberculosis fibrosis and lung cancer. Silencing of NOX4 signaling in tuberculous fibrosis reduced the metastatic potential by enhancing autophagy in both in vivoand in vitro studies. This result suggests that NOX4-P62 might serve as a therapeutic target for tuberculous fibrosis-associated lung cancer.While a higher incidence of lung cancer in subjects with previous tuberculous infection has been reported in epidemiologic data, the mechanism by which previous tuberculosis affects lung cancer remains unclear. We investigated the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.Heat-killed Mycobacterium tuberculosis-stimulated mesothelial cells augmented the migrationand invasive potential of lung cancer cells in a NOX4-dependent manner. Mice with Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection exhibited increased expression of NOX4 and enhanced malignant potential of lung cancer compared to mice with intrathoracic injection of phosphate-buffered saline. The BCG+ KLN205 (KLN205 cancer cell injection after BCG treatment) NOX4 KO mice group showed reduced tuberculous fibrosis-promoted metastatic potential of lung cancer, increased autophagy, and decreased expression of TGF-β, IL-6, and TNF-α compared to the BCG+KLN205 WT mice group. Finally, NOX4 silencing mitigated the malignant potential of A549 cells that was enhanced by tuberculous pleural effusion and restored autophagy signaling. Our results suggest that the NOX4–autophagy axis regulated by tuberculous fibrosis could result in enhanced tumorigenic potential and that NOX4-P62 might serve as a target for tuberculous fibrosis-induced lung cancer.

CUEDC1 inhibits epithelial-mesenchymal transition via the TβRI/Smad signaling pathway and suppresses tumor progression in non-small cell lung cancer.

Lung cancer remains the most lethal cancer worldwide because of its high metastasis potential. Epithelial-mesenchymal transition (EMT) is known as the first step of the metastasis cascade, but the potential regulatory mechanisms of EMT have not been clearly established. In this study, we first found that low CUEDC1 expression correlated with lymph node metastasis in non-small cell lung cancer (NSCLC) patients using immunohistochemistry (IHC). CUEDC1 knockdown promoted the metastasis of NSCLC cells and EMT process and activated TβRI/Smad signaling pathway. Overexpression of CUEDC1 decreased the metastatic potential of lung cancer cells and inhibited the EMT process and inactivated TβRI/Smad signaling pathway. Immunoprecipitation (IP) assays showed that Smurf2 is a novel CUEDC1-interacting protein. Furthermore, CUEDC1 could regulate Smurf2 expression through the degradation of Smurf2. Overexpression of Smurf2 abolished CUEDC1 knockdown induced-EMT and the activation of TβRI/Smad signaling pathway, while siRNA Smurf2 reversed CUEDC1 overexpression-mediated regulation of EMT and TβRI/Smad signaling pathway. Additionally, CUEDC1 inhibited proliferation and promoted apoptosis of NSCLC cells. In vivo, CUEDC1-knockdown cells promoted metastasis and tumor growth compared with control cells. In conclusion, our findings indicate that the crucial role of CUEDC1 in NSCLC progression and provide support for its clinical investigation for therapeutic approaches.

Sub-acute Toxicity Assessment of Taxol Isolated From Fusarium Solani, an Endophytic Fungus of Taxus Brevifolia, in Wistar Rats and Analyzing Its Cytotoxicity and Apoptotic Potential in Lung Cancer Cells.

The limited availability of taxol from plant sources has prompted the scientific world to look for an alternative, as in the chemical synthesis of tissue cultures of the Taxus species, to meet the increasing demand for the drug. However, these alternative means are expensive or result in low yield. Previously, we have reported that Fusarium solani isolated from Taxus celebica produced taxol and its precursor baccatin III in liquid-grown cultures, and it exhibited promising anticancerous effects in certain cancer cell lines. In the present study, we examined the sub-acute toxicity of fungal taxol (FS) in Wistar rats according to the Organization for Economic Co-operation and Development (OECD) guidelines. The sub-acute oral administration of FS up to 500 mg/kg for a period of 28 days appears to be safe in rats and did not cause severe treatment-related toxicity or treatment-related death. The observed changes in body weight, histopathology, hematological and biochemical parameters, and organ weight were not significant compared to those in the control group of animals. The results suggest that FS is relatively safe when administered orally in rats. The antiproliferative and apoptosis-inducing activities were studied in A549 (human lung cancer) cell line. FS arrested the cells at S and G2/M phases, leading to apoptosis. The characteristic molecular signatures of apoptosis, such as externalized phosphatidyl serine, DNA fragmentation, and nuclear and chromatin condensation, were observed upon FS treatment. FS triggered the generation of reactive oxygen species in A549 cells and elicited cell death by both extrinsic as well as the mitochondria-mediated intrinsic pathway of apoptosis. These results indicate that endophytic fungi isolated from medicinal plants may serve as potential sources of anticancerous compounds with little side effects.

Abstract 1247: NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic potential

Abstract Background Increased incidence of lung cancer in subjects with previous tuberculous infection was reported in epidemiologic data. NOX4 signaling contributes to tuberculous pleural fibrosis and lung cancer proliferation, respectively. The objective of this study was to investigate the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo. Methods After pleural mesothelial cells from WT and NOX4 KO C57BL/6 mice were stimulated with Heat-Killed mycobacterium tuberculosis (HKMT) for 24 hour, cellular interactions between mesothelial cell and cancer cell were evaluated by using transwell invasion assay and wound healing assay. A murine model injected with cancer at 4 weeks after Mycobacterium bovis bacillus Calmette-Guérin (BCG) pleural infection were used to validate the contribution of tuberculous fibrosis to tumor invasion. Results HKMT -stimulated mesothelial cells induced enhanced invasion and migration potential of lung cancer cells in a NOX4-dependent manner. The inhibition of NOX4 signaling exerted a negative effect on the metastatic potential of lung cancer by tuberculous fibrosis in mice model. The expression of inflammatory cytokines like TNF-a, TGF-β and IL-6 was enhanced in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA. The expression of P62 in lung tissue was higher in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA. Discussions Our results suggest that NOX4 and autophagy signaling changed by tuberculous fibrosis could result enhanced tumorigenic potential. NOX4-P62 might seve as a target for the development of anti-tuberculous fibrosis and anti-cancer drugs. Citation Format: Yoonki Hong, Seong-Ji Woo, Youngmi Kim, Ji Young Hong. NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1247.

Repurposing Calsyntenin‐1 as a modulator in FSTL1‐mediated Lung Adenocarcinoma Metastasis: The Crosstalk with extracellular ALDOA

Previously, we found that FSTL1 downregulation strongly predicts a poorer prognosis in patients with lung adenocarcinoma, but not squamous‐cell carcinoma, and highly correlates with an increased metastatic potential of lung cancer cells in vitro and in vivo. To examine detail molecular mechanisms, we presented protein‐protein interaction (PPI) assays. Several proteins that belong to extracellular or exosomal members were identified by mass spectrometric analysis from the FSTL1‐interacting protein mixture. In our data, we found that CLSTN1 ranked first. CLSTN1, calsyntenin‐1, is a type‐1 neuronal transmembrane protein, which is in the postsynaptic membrane. CLSTN1 was originally identified as a transmitted protein that modulated synaptic signals with proteolytic cleavage fragment. Recent research showed that CLSTN1 overexpressed in lung adenocarcinoma tissue and released to serum. But the molecular mechanisms of CLSTN1 in lung cancer still need to be confirmed. Extracellular ALDOA was detected in lung cancer cell conditioned medium. The detail functions and mechanism of extracellular ALDOA in lung adenocarcinoma is still unclear. CLSTN1 expression in cultured medium was positive correlation with ALDOA expression in cultured medium. Collectively, we may repurpose CLSTN1 as a modulator to regulate lung adenocarcinoma metastasis and their networking, which can be used in combination with targeted therapies, chemotherapies, or radical therapies in future research.

Circulating microRNA-590-5p functions as a liquid biopsy marker in non-small cell lung cancer.

Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR‐590‐5p as a potential prognostic marker in the progression of non‐small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real‐time PCR. Our data showed an ~7.5‐fold downregulation of miR‐590‐5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR‐590‐5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial‐to‐mesenchymal transition negatively correlated with miR‐590‐5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual‐luciferase reporter assays identified STAT3 as a direct target of miR‐590‐5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c‐Myc, Vimentin, and β‐catenin) involved in tumorigenesis. Taken together, our study suggests that miR‐590‐5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.

Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis.

An increasing number of enzymes involved in serine biosynthesis have been identified and correlated with malignant evolution in various types of cancer. Here we showed that the overexpression of phosphoserine aminotransferase 1 (PSAT1) is widely found in lung cancer tissues compared with nontumor tissues and predicts a poorer prognosis in patients with lung adenocarcinoma. PSAT1 expression was examined in a tissue microarray by immunohistochemistry. The data show that the knockdown of PSAT1 dramatically inhibits the in vitro and in vivo metastatic potential of highly metastatic lung cancer cells; conversely, the enforced expression of exogenous PSAT1 predominantly enhances the metastatic potential of lung cancer cells. Importantly, manipulating PSAT1 expression regulates the in vivo tumor metastatic abilities in lung cancer cells. Adjusting the glucose and glutamine concentrations did not alter the PSAT1-driven cell invasion properties, indicating that this process might not rely on the activation of its enzymatic function. RNA microarray analysis of transcriptional profiling from PSAT1 alternation in CL1-5 and CL1-0 cells demonstrated that interferon regulatory factor 1 (IRF1) acts as a crucial regulator of PSAT1-induced gene expression upon metastatic progression. Decreasing the IRF1-IFIH1 axis compromised the PSAT1-prompted transcriptional reprogramming in cancer cells. Our results identify PSAT1 as a key regulator by a novel PSAT1/IRF1 axis in lung cancer progression, which may serve as a potential biomarker and therapeutic target for the treatment of lung cancer patients.