A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma.
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ABSTRACT:
SUBMITTER: Tan X
PROVIDER: S-EPMC7773359 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mitochondrial pyruvate carrier 1 (MPC1), a key factor that controls pyruvate transportation in the mitochondria, is known to be frequently dysregulated in tumor initiation and progression. However, the clinical relevance and potential molecular mechanisms of MPC1 in lung adenocarcinoma (LAC) progression remain to be illustrated. Herein, MPC1 was lowly expressed in LAC tissues and significantly associated with favorable survival of patients with LAC. Functionally, MPC1 markedly suppressed stemness, invasion, and migration in vitro and spreading growth of LAC cells in vivo. Further study revealed that MPC1 could interact with mitochondrial signal transducer and activator of transcription 3 (mito-STAT3), disrupting the distribution of STAT3 and reducing cytoplasmic signal transducer and activator of transcription 3 (cyto-STAT3) as well as its phosphorylation, while the activation of cyto-STAT3 by IL-6 reversed the attenuated malignant progression in MPC1-overexpression LAC cells. Collectively, we reveal that MPC1/STAT3 axis plays an important role in the progression of LAC, and our work may promote the development of new therapeutic strategies for LAC.
| S-EPMC6377639 | biostudies-literature
Project description:Background:Statins have anticancer properties by acting as competitive inhibitors of the mevalonate pathway. They also have anti-inflammatory activity, but their role in suppressing inflammation in a cancer context has not been investigated to date. Methods:We have analyzed the relationship between statin use and tumor-associated macrophages (TAMs) in a cohort of 262 surgically resected primary human lung adenocarcinomas. TAMs were evaluated by multiplex immunostaining for the CD68 pan-TAM marker and the CD163 protumorigenic TAM marker followed by digital slide scanning and partially automated quantitation. Links between statin use and tumor stage, virulence, and cancer-specific survival were also investigated in a wider cohort of 958 lung adenocarcinoma cases. All statistical tests were two-sided. Results:We found a statin dose-dependent reduction in protumorigenic TAMs (CD68+CD163+) in both stromal (P?=?.021) and parenchymal (P?=?.003) compartments within regions of in situ tumor growth, but this association was lost in invasive regions. No statistically significant relationship between statin use and tumor stage was observed, but there was a statin dose-dependent shift towards lower histological grade as assessed by growth pattern (P?=?.028). However, statin use was a predictor of slightly worse cancer-specific survival (P?=?.032), even after accounting for prognostic variables in a multivariable Cox proportional hazards survival model (hazard ratio?=?1.38, 95% confidence interval = 1.04 to 1.84). Conclusions:Statin use is associated with reduced numbers of protumorigenic TAMs within preinvasive lung adenocarcinoma and is related to reduced tumor invasiveness, suggesting a chemo-preventive effect in early tumor development. However, invasive disease is resistant to these effects, and no beneficial relationship between statin use and patient outcome is observed.
| S-EPMC7068793 | biostudies-literature
Project description:BackgroundUbiquitin-conjugating enzyme E2T (UBE2T) acts as an oncogene in various types of cancer. However, the mechanisms behind its oncogenic role remain unclear in lung cancer. This study aims to explore the function and clinical relevance of UBE2T in lung cancer.MethodsLentiviral vectors were used to mediate UBE2T depletion or overexpress UBE2T in lung cancer cells. CCK8 analysis and western blotting were performed to investigate the effects of UBE2T on proliferation, autophagy, and relevant signaling pathways. To exploit the clinical significance of UBE2T, we performed immunohistochemistry staining with an anti-UBE2T antibody on 131 NSCLC samples. Moreover, we downloaded the human lung adenocarcinoma (LUAD) dataset from The Cancer Atlas Project (TCGA). Lasso Cox regression model was adopted to establish a prognostic model with UBE2T-correlated autophagy genes.ResultsWe found that UBE2T stimulated proliferation and autophagy, and silencing this gene abolished autophagy in lung cancer cells. As suggested by Gene set enrichment analysis, we observed that UBE2T downregulated p53 levels in A549 cells and vice versa. Blockade of p53 counteracted the inhibitory effects of UBE2T depletion on autophagy. Meanwhile, the AMPK/mTOR signaling pathway was activated during UBE2T-mediated autophagy, suggesting that UBE2T promotes autophagy via the p53/AMPK/mTOR pathway. Interestingly, UBE2T overexpression increased cisplatin-trigged autophagy and led to cisplatin resistance of A549 cells, whereas inhibiting autophagy reversed drug resistance. However, no association was observed between UEB2T and overall survival in a population of 131 resectable NSCLC patients. Therefore, we developed and validated a multiple gene signature by considering UBE2T and its relevance in autophagy in lung cancer. The risk score derived from the prognostic signature significantly stratified LUAD patients into low- and high-risk groups with different overall survival. The risk score might independently predict prognosis. Interestingly, nomogram and decision curve analysis demonstrated that the signature's prognostic accuracy culminated while combined with clinical features. Finally, the risk score showed great potential in predicting clinical chemosensitivity.ConclusionsWe found that UBE2T upregulates autophagy in NSCLC cells by activating the p53/AMPK/mTOR signaling pathway. The clinical predicting ability of UBE2T in LUAD can be improved by considering the autophagy-regulatory role of UBE2T.
| S-EPMC8407090 | biostudies-literature
Project description:Background: Lung cancer is associated with the highest mortality rate of all cancer types, and the most common histologic subtype of lung cancer is adenocarcinoma. To apply more effective therapeutic treatment, molecular markers that are able to predict the recurrence risk of patients with adenocarcinoma are critically needed. Mutations in TP53 tumor suppressor gene have been found in approximately 50% of lung adenocarcinoma cases, but the presence of a TP53 mutation does not always associate with increased mortality.Methods: The Cancer Genome Atlas RNA sequencing data of lung adenocarcinoma were used to define a novel gene signature for P53 deficiency. This signature was then used to calculate a sample-specific P53 deficiency score based on a patient's transcriptomic profile and tested in four independent lung adenocarcinoma microarray datasets.Results: In all datasets, P53 deficiency score was a significant predictor for recurrence-free survival where high P53 deficiency score was associated with poor survival. The score was prognostic even after adjusting for several key clinical variables including age, tumor stage, smoking status, and P53 mutation status. Furthermore, the score was able to predict recurrence-free survival in patients with stage I adenocarcinoma and was also associated with smoking status.Conclusions: The P53 deficiency score was a better predictor of recurrence-free survival compared with P53 mutation status and provided additional prognostic values to established clinical factors.Impact: The P53 deficiency score can be used to stratify early-stage patients into subgroups based on their risk of recurrence for aiding physicians to decide personalized therapeutic treatment. Cancer Epidemiol Biomarkers Prev; 27(1); 86-95. ©2017 AACR.
| S-EPMC5839302 | biostudies-literature
Project description:Growing incidence of lung adenocarcinoma (LUAD) has been detected recently. Multiple long non-coding RNAs (lncRNAs) have been proven as tumor facilitators or inhibitors by extensive works. Present study concentrated on characterizing the potential role of LINC01123 in LUAD. We explored the differential expression of LINC01123 through qRT-PCR and found the amplification of LINC01123 in LUAD cell lines. It was ascertained that LINC01123 was definitely responsible for the malignant processes of LUAD cells. Further, we validated the ceRNA network of LINC01123/miR-449b-5p/NOTCH1 in LUAD via mechanical experiments. As a transcriptional factor related to epithelial mesenchymal transition (EMT), ZEB1 was responsible for the transcriptional activation of both LINC01123 and NOTCH1. The involvement of NOTCH signaling in LUAD was interrogated through evaluating functional changes after treating with FLI-06 (NOTCH pathway suppressor). It showed that FLI-06-caused NOTCH signaling inactivation suppressed malignant functions in LUAD cells. Additionally, LINC01123 facilitated NOTCH1-dependent NOTCH signaling activation. Rescue experiments probed the modulatory function of LINC01123/miR-449b-5p/NOTCH1 in LUAD cellular processes. Altogether, ZEB1-activated LINC01123 accelerates the malignancy in LUAD through miR-449b-5p/NOTCH1 axis-mediated NOTCH signaling pathway, while NOTCH1 boosts ZEB1 in return. These observations suggest the huge potential of LINC01123 as a new target for LUAD therapy.
| S-EPMC7667157 | biostudies-literature
Project description:RationaleCC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.ObjectivesTo determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.MethodsUsing human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.Measurements and main resultsWe observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.ConclusionsOur findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.
| S-EPMC6363971 | biostudies-literature
Project description:Simultaneous P53 loss and activation of the PTEN-restricted PI3K-AKT pathway frequently occur in aggressive breast cancers. P53 loss causes genome instability, while PTEN loss and/or activating mutations of PIK3CA and AKT promote cancer cell proliferation that also increases incidences of genomic aberrations. However, the genomic alterations associated with P53 loss and activated PTEN-PI3K-AKT signaling in breast cancer have not been defined. Spatiotemporally controlled breast cancer models with inactivation of both P53 and Pten in adult mice have not been established for studying genomic alterations. Herein, we deleted both floxed Pten and Tp53 genes in the mammary gland epithelial cells in adult mice using a RCAS virus-mediated Cre-expressing system. These mice developed small tumors in 21 weeks, and poorly differentiated larger tumors in 26 weeks. In these tumors, we identified 360 genes mutated by nonsynonymous point mutations and small insertions and deletions (NSPMs/InDels), 435 genes altered by copy number amplifications (CNAs), and 450 genes inactivated by copy number deletions (CNDs). Importantly, 22.2%, 75.9% and 27.3% of these genes were also altered in human breast tumors with P53 and PTEN losses or P53 loss and activated PI3K-AKT signaling by NSPMs/InDels, CNAs and CNDs, respectively. Therefore, inactivation of P53 and Pten in adult mice causes rapid-growing breast tumors, and these tumors recapitulate a significant number of genetic aberrations in human breast tumors with inactivated P53 and activated PTEN-PI3K-AKT signaling. Further characterization of these commonly altered genes in breast cancer should help to identify novel cancer-driving genes and molecular targets for developing therapeutics.
| S-EPMC8692138 | biostudies-literature
Project description:The underlying mechanisms of long non-coding RNAs (lncRNA) participating in the progression of lung cancers are largely unknown. We found a novel lncRNA, PIK3CD antisense RNA 2 (PIK3CD-AS2), that contributes to lung adenocarcinoma (LUAD) progression. The expression characteristics of PIK3CD-AS2 in LUAD were analyzed using microarray expression profile, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and validated in 92 paired LUAD tissues by chromogenic in situ hybridization. Our data confirmed that PIK3CD-AS2 expression is a crucial regulator of LUAD progression and associated with shorter patient survival. In vitro studies showed that PIK3CD-AS2 increased cell growth and slowed apoptosis in p53wt cells but not in p53null cells. Mechanically, it is demonstrated that PIK3CD-AS2 bound to and maintained the stability of Y-box binding protein 1 (YBX1), a potent destabilizer of p53, by impeding its ubiquitination and degradation. Downexpression of YBX1 reversed PIK3CD-AS2-mediated inhibition of p53 signaling. Additionally, the therapeutic effect evaluation of a locked nuclear acid (LNA) specifically targeting PIK3CD-AS2 showed an anti-tumor activity in mice with A549 cells xenograft and p53 wild-type LUAD patient-derived tumor xenograft (PDTX) model. Clinically, the high expression of PIK3CD-AS2 showed a poor disease-free survival in p53 wild-type patients in TCGA database. Our findings suggest that PIK3CD-AS2 regulates LUAD progression and elucidate a new PIK3CD-AS2/YBX1/p53 signaling axis, providing a potential lncRNA-directed therapeutic strategy especially in p53 wild-type LUAD patients.
| S-EPMC7067885 | biostudies-literature
Project description:The p53-inducible gene 3 (PIG3) is one of the p53-induced genes at the onset of apoptosis, which plays an important role in cell apoptosis and DNA damage response. Our previous study reported an oncogenic role of PIG3 associated with tumor progression and metastasis in non-small cell lung cancer (NSCLC). In this study, we further analyzed PIG3 mRNA expression in 504 lung adenocarcinoma (LUAD) and 501 lung squamous cell carcinoma (LUSC) tissues from The Cancer Genome Atlas database and we found that PIG3 expression was significantly higher in LUAD with lymph node metastasis than those without, while no difference was observed between samples with and without lymph node metastasis in LUSC. Gain and loss of function experiments were performed to confirm the metastatic role of PIG3 in vitro and to explore the mechanism involved in its oncogenic role in NSCLC metastasis. The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho-focal adhesion kinase (FAK) and phospho-Src kinase expression, while its overexpression resulted in the opposite effects. Blocking FAK with its inhibitor reverses PIG3 overexpression-induced cell motility in NSCLC cells, indicating that PIG3 increased cell metastasis through the FAK/Src/paxillin pathway. Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor. In conclusion, our data revealed a role for PIG3 in inducing LUAD metastasis, and its role as a new FAK regulator, suggesting that it could be considered as a novel prognostic biomarker or therapeutic target in the treatment of LUAD metastasis.
| S-EPMC6272089 | biostudies-literature
Project description:p53 is commonly mutated in lung adenocarcinoma. Mutant p53 loses wild-type function and some missense mutations further acquire oncogenic functions, while p53 wild-type may also induce pro-survival signaling. Therefore identification of signatures based on p53 mutational status has relevance to our understanding of p53 signaling pathways in cancer and identification of new therapeutic targets. To this end, we compared proteomic profiles of three cellular compartments (whole-cell extract, cell surface, and media) from 28 human lung adenocarcinoma cell lines that differ based on p53 mutational status. In total, 11,598, 11,569, and 9090 protein forms were identified in whole-cell extract, cell surface, and media, respectively. Bioinformatic analysis revealed that representative pathways associated with epithelial adhesion, immune and stromal cells, and mitochondrial function were highly significant in p53 missense mutations, p53 loss and wild-type p53 cell lines, respectively. Of note, mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-?), a transcription coactivator that promotes mitochondrial oxidative phosphorylation and mitochondrial biogenesis, was substantially higher in p53 wild-type cell lines compared to either cell lines with p53 loss or with missense mutation. Small interfering RNA targeting PGC1-? inhibited cell proliferation in p53 wild-type cell lines, indicative of PGC1-? and its downstream molecules as potential therapeutic targets in p53 wild-type lung adenocarcinoma.
| S-EPMC4403731 | biostudies-literature