ABSTRACT
OBJECTIVE: This study investigates the correlation between serum levels of YKL-40, LXRs, PPM1A, and TGF-ß1 and airway remodeling and lung function in bronchial asthma patients. METHODS: The study involved 80 bronchial asthma patients and 92 healthy individuals. Serum cytokines, airway remodeling, and lung function markers were compared across mild, moderate, and severe asthma cases using high-resolution CT, t-tests, ANOVA, and Pearson correlation analysis. RESULTS: Asthmatic patients exhibited higher levels of serum YKL-40, LXRα, LXRß, TGF-ß1, airway wall thickness (T)/outer diameter (D), and WA% of total cross-sectional area compared to controls. Conversely, their serum PPM1A, Peak Expiratory Flow (PEF), and Forced Expiratory Volume in 1 s (FEV1) were lower. Serum YKL-40 and TGF-ß1 levels were positively correlated with T/D and WA%, and negatively correlated with PEF and FEV1. PPM1A levels were strongly associated with T/D, WA%, PEF, and FEV1. CONCLUSION: The severity of bronchial asthma is associated with increased serum levels of YKL-40, LXRα, LXRß, and TGF-ß1 and decreased PPM1A. The levels of YKL-40, PPM1A, and TGF-ß1 have a significant correlation with airway remodeling and lung function.
Subject(s)
Airway Remodeling , Asthma , Chitinase-3-Like Protein 1 , Liver X Receptors , Protein Phosphatase 2C , Respiratory Function Tests , Transforming Growth Factor beta1 , Humans , Asthma/blood , Asthma/physiopathology , Chitinase-3-Like Protein 1/blood , Airway Remodeling/physiology , Male , Female , Transforming Growth Factor beta1/blood , Liver X Receptors/blood , Adult , Middle Aged , Protein Phosphatase 2C/blood , Biomarkers/blood , Lung/physiopathology , Lung/diagnostic imaging , Severity of Illness Index , Case-Control Studies , Forced Expiratory VolumeABSTRACT
BACKGROUND: PPM1D (Protein phosphatase magnesium-dependent 1δ) is known as a damage response regulator, a part of the p53 negative feedback loop. Truncating mutations of PPM1D, resulting in overexpression, are frequently found in the blood of patients with breast or ovarian cancer. To identify whether the PPM1D mutation predisposes patients to such cancers or if it results from the cancer and therapy, somatic PPM1D mutations in association with previous cancer and chemotherapy need to be explored. METHODS: We performed next-generation sequencing (NGS) analysis of blood samples from patients suspected to have hereditary cancer. We grouped the patients according to their diagnoses and history of chemotherapy. For the patients with PPM1D mutations in blood, tumor tissue specimens were examined for the PPM1D mutation using conventional sequencing. RESULTS: A total of 1,195 patients, including 719 patients with breast cancer and 240 with ovarian cancer, were tested, and four (~0.3%) had the truncating mutation in PPM1D. All truncating mutations were in exon 6, in mosaic form, with a mean allele fraction of 11.15%. While 395 out of the 1,195 patients had undergone chemotherapy, the four with the truncating mutation had a history of cisplatin-based chemotherapy. No corresponding mutations were identified in the tumor tissues. CONCLUSIONS: We investigated the frequency of the somatic mosaic PPM1D mutation, in patients with breast or ovarian cancer, which is suggested to be low and related to a history of cisplatin-based chemotherapy. It may be a marker of previous exposure to selective pressure for cells with an impaired DNA damage response.
Subject(s)
Breast Neoplasms, Male , Cisplatin/administration & dosage , Mosaicism , Neoplasm Proteins , Neoplastic Syndromes, Hereditary , Ovarian Neoplasms , Protein Phosphatase 2C , Aged , Aged, 80 and over , Breast Neoplasms, Male/blood , Breast Neoplasms, Male/drug therapy , Breast Neoplasms, Male/genetics , Female , Humans , Male , Middle Aged , Neoplasm Proteins/blood , Neoplasm Proteins/genetics , Neoplastic Syndromes, Hereditary/blood , Neoplastic Syndromes, Hereditary/drug therapy , Neoplastic Syndromes, Hereditary/genetics , Ovarian Neoplasms/blood , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Protein Phosphatase 2C/blood , Protein Phosphatase 2C/geneticsABSTRACT
Hepatocellular carcinoma (HCC) is a lethal liver malignancy worldwide. In this study, we reported that protein phosphatase magnesium-dependent 1δ (PPM1D) was highly expressed in the majority of HCC cases (approximately 59%) and significantly associated with high serum α-fetoprotein (AFP) level (P = 0.044). Kaplan- Meier and Cox regression data indicated that PPM1D overexpression was an independent predictor of HCCspecific overall survival (HR, 2.799; 95% CI, 1.346-5.818, P = 0.006). Overexpressing PPM1D promoted cell viability and invasion, whereas RNA interference-mediated knockdown of PPM1D inhibited proliferation, invasion, and migration of cultured HCC cells. In addition, PPM1D suppression by small interfering RNA decreased the tumorigenicity of HCC cells in vivo. Overall, results suggest that PPM1D is a potential prognostic marker and therapeutic target for HCC.
