transforming-growth-factor-beta and Small-Cell-Lung-Carcinoma

Nowadays, the impact of the tumor-immune microenvironment (TME) in non-small-cell lung cancer (NSCLC) prognosis and treatment response remains unclear. Thus, we evaluated the expression of PD-L1, tumor-infiltrating lymphocytes (TILs), and transforming growth factor beta (TGF-β) in NSCLC to identify differences in TME, detect possible new prognostic factors, and assess their relationship. We retrospectively analyzed 55 samples from patients who underwent NSCLC surgery and had over a 5-year follow-up. PD-L1 expression was determined by immunohistochemistry following standard techniques. The presence of TILs was evaluated at low magnification and classified into two categories, “intense” and “non-intense”. Cytoplasmic TGF-β staining visualization was divided into four categories, and unequivocal nuclear staining in >1% of viable tumor cells was defined as “present” or “absent”. Our aim was to identify differences in disease-free survival (DFS) and overall survival (OS). Tumor stage was the only objective prognostic factor for OS. PD-L1 expression and the presence of TILs had no prognostic impact, neither their combination. There seems to be a lower expression of PD-L1 and a higher expression of TILs in early stages of the disease. Our TGF-β nuclear staining analysis was promising, since it was associated with worse DFS, revealing this protein as a possible prognostic biomarker of recurrence for resectable NSCLC.

Topics: B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Recurrence; Retrospective Studies; Risk Factors; Small Cell Lung Carcinoma; Staining and Labeling; Transforming Growth Factor beta; Tumor Microenvironment

Topics: Alternative Splicing; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Etoposide; Female; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Protein-Arginine N-Methyltransferases; RNA-Binding Proteins; RNA, Messenger; Signal Transduction; Smad7 Protein; Small Cell Lung Carcinoma; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Circular RNAs (circRNAs) are novel RNA molecules that play important roles in chemoresistance in different cancers, including breast and gastric cancers. However, whether circRNAs are involved in the response to chemotherapy in small cell lung cancer (SCLC) remains largely unknown. In this study, we observed that cESRP1 (circular RNA epithelial splicing regulatory protein-1) expression was significantly downregulated in the chemoresistant cells compared with the parental chemosensitive cells. cESRP1 enhanced drug sensitivity by repressing miR-93-5p in SCLC. Cytoplasmic cESRP1 could directly bind to miR-93-5p and inhibit the posttranscriptional repression mediated by miR-93-5p, thereby upregulating the expression of the miR-93-5p downstream targets Smad7/p21(CDKN1A) and forming a negative feedback loop to regulate transforming growth factor-β (TGF-β) mediated epithelial-mesenchymal transition. Furthermore, cESRP1 overexpression and TGF-β pathway inhibition both altered tumour responsiveness to chemotherapy in an acquired chemoresistant patient-derived xenograft model. Importantly, cESRP1 expression was downregulated in SCLC patient tissues and was associated with survival. Our findings reveal, for the first time, that cESRP1 plays crucial a role in SCLC chemosensitivity by sponging miR-93-5p to inhibit the TGF-β pathway, suggesting that cESRP1 may serve as a valuable prognostic biomarker and a potential therapeutic target in SCLC patients.

Topics: Animals; Base Sequence; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; RNA, Circular; Signal Transduction; Smad7 Protein; Small Cell Lung Carcinoma; Transforming Growth Factor beta; Xenograft Model Antitumor Assays

Most lung cancer (LC) patients have metastatic disease at time of diagnosis, which influence the treatment regimen and is the most important prognostic factor. The main purpose of our study was to evaluate the relationship between cell proliferation (Ki-67 label index), p53, transforming growth factor-β (TGF-β) and lysyl oxidase (LOX), and the metastatic stages of different lung cancers. The secondary aim was to correlate these parameters with the standardized uptake value (SUVmax) of the primary lesion during positron emission tomography-computed tomography (PET-CT).. Eighty-five treatment-naive patients with LC were enrolled. All patients were examined with PET-CT. Ki-67, p53, TGF-β and LOX were evaluated histopathologically.. Small cell lung cancer (SCLC) showed the most intense staining in all parameters. A well-differentiated adenocarcinoma (AC) demonstrated a more diffuse and intense staining than squamous cell carcinoma (SCC). There was no statistically significant relationship between the four parameters and metastases of SCLC and SCC. However, a significant relationship between TGF-β, LOX and metastatic AC was demonstrated with regards to diffusivity and intensity. p53 and Ki-67 did not show a significant relationship. No correlation between SCLC and SCC and SUVmax was found. However, in AC, the diffusivity and intensity of the LOX and p53 staining showed a statistically significant relationship to the SUVmax.. LOX and TGF-β may play roles in metastatic AC. LOX and TGF-β may become markers of metastatic disease and inhibition could be explored for treatment.

Topics: Carcinoma, Non-Small-Cell Lung; Cohort Studies; Female; Fluorodeoxyglucose F18; Humans; Ki-67 Antigen; Lung Neoplasms; Male; Multimodal Imaging; Positron-Emission Tomography; Protein-Lysine 6-Oxidase; Radiopharmaceuticals; Small Cell Lung Carcinoma; Tomography, X-Ray Computed; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Epidemiologic studies have shown that most cases of lung cancers (85%-90%) are directly attributable to cigarette smoking. Although much information has been gained about the effects of cigarette smoking on various signaling pathways causing lung cancer, nothing is known about the effect of cigarette smoking on the TGF-β-induced tumor suppressor function in lung cancer. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated with cigarette smoke condensate (CSC) and dimethyl sulfoxide (as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-β-mediated transcription due to reduced expression of Smad3. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-β-mediated growth inhibition, and enhanced tumorigenicity. The decrease in apoptosis is due to the upregulation of Bcl-2, which is a downstream target of Smad3. Re-expression of Smad3 in the CSC-treated cells restored TGF-β signaling, increased apoptosis, and decreased cell viability and tumorigenicity. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability, and increased TGF-β-mediated growth inhibition. Expression of Smad3 is lower in lung tumors of current smokers than that observed in never-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-β-mediated growth inhibition and apoptosis by reducing expression of Smad3.

Topics: Acetylation; Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Bronchi; Carcinoma, Squamous Cell; Cell Proliferation; Cells, Cultured; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Histones; Humans; Immunoenzyme Techniques; Immunoprecipitation; Lung Neoplasms; Mice; Mice, Nude; Phosphorylation; Protein Binding; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Smad3 Protein; Small Cell Lung Carcinoma; Smoking; Survival Rate; Tissue Array Analysis; Transcription, Genetic; Transforming Growth Factor beta