HIF1A-dependent overexpression of MTFP1 promotes lung squamous cell carcinoma development by activating the glycolysis pathway.

Introduction: Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein implicated in the development and progression of various tumors, particularly lung squamous cell carcinoma (LUSC). This study aims to provide a more theoretical basis for the treatment of LUSC. Methods: Through bioinformatics analysis, MTFP1 was identified as a novel target gene of HIF1A. MTFP1 expression in LUSC was examined using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Proteomics Data Commons (PDC) databases. The Kaplan-Meier plotter (KM plotter) database was utilized to evaluate its correlation with patient survival. Western blot and chromatin immunoprecipitation (ChIP) assays were employed to confirm the regulatory relationship between MTFP1 and HIF1A. Additionally, cell proliferation, colony formation, and migration assays were conducted to investigate the mechanism by which MTFP1 enhances LUSC cell proliferation and metastasis. Results: Our findings revealed that MTFP1 overexpression correlated with poor prognosis in LUSC patients(P < 0.05). Moreover, MTFP1 was closely associated with hypoxia and glycolysis in LUSC (R = 0.203; P < 0.001, R = 0.391; P < 0.001). HIF1A was identified as a positive regulator of MTFP1. Functional enrichment analysis demonstrated that MTFP1 played a role in controlling LUSC cell proliferation. Cell proliferation, colony formation, and migration assays indicated that MTFP1 promoted LUSC cell proliferation and metastasis by activating the glycolytic pathway (P < 0.05). Conclusions: This study establishes MTFP1 as a novel HIF1A target gene that promotes LUSC growth by activating the glycolytic pathway. Investigating MTFP1 may contribute to the development of effective therapies for LUSC patients, particularly those lacking targeted oncogene therapies.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

The Role Played by Mitochondria in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) refers to an endocrine disorder syndrome that are correlated with multiple organs and systems. PCOS has an effect on women at all stages of their lives, and it has an incidence nearly ranging from 6% to 20% worldwide. Mitochondrial dysfunctions (e.g., oxidative stress, dynamic imbalance, and abnormal quality control system) have been identified in patients and animal models of PCOS, and the above processes may play a certain role in the development of PCOS and its associated complications. However, their specific pathogenic roles should be investigated in depth. In this review, recent studies on the mechanisms of action of mitochondrial dysfunction in PCOS and its associated clinical manifestations are summarized from the perspective of tissues and organs, and some studies on the treatment of the disease by improving mitochondrial function are reviewed to highlight key role of mitochondrial dysfunction in this syndrome.

A study of the correlation between total lung volume and the percent of low attenuation volume and PFT indicators in patients with preoperative lung cancer.

The objective was to explore the relationships between computed tomography (CT) lung volume parameters and pulmonary function test (PFT) indexes and develop predictive scores to predict PFT indexes in Chinese preoperative patients suspected with lung cancer. Preoperative patients suspected with lung cancer aged 18 years or more and examined by chest CT scan and PET were consecutively recruited from April to August 2020, at Yunnan Cancer Hospital. CT and PET data were selected from medical record. Pearson correlation was used to explore the relationships between CT parameters and PFT indexes. Predictive scores of PFT indexes were developed from unstandardized coefficients of linear regression models of using CT parameters as predictors. The assessments of predictive ability of scores were conducted by receiver operating characteristics curves. A total of 124 preoperative patients suspected with lung cancer participated in this study. Total lung volume significantly correlated with total lung capacity (r = 0.708), residual volume (r = 0.411), forced expiratory volume in one second (FEV1, r = 0.535), forced vital capacity (FVC, r = 0.687), and FEV1/FVC (r = -0.319). Percent of low attenuation volume significantly correlated with total lung capacity (r = 0.200), residual volume (r = 0.215), FEV1 percentage of predictive value (FEV1%, r = -0.204) and FEV1/FVC (r = -0.345). Four predictive scores for FEV1, FEV1%, FEV1/FVC and FVC% were developed. The area under the curve of receiver operating characteristics for FEV1 <2L, FEV1% <80%, FEV1/FVC <80% and FVC% <80% were 0.856, 0.667, 0.749 and 0.715, respectively. A prediction of poor lung function in preoperative patients suspected with lung cancer, using total lung volume and percent of low attenuation volume was possible. The predictive scores should be further evaluated for external validity.

USP14 regulates heme metabolism and ovarian cancer invasion through BACH1 deubiquitination and stabilization.

The deubiquitinating enzyme USP14 has been established as a crucial regulator in various diseases, including tumors, neurodegenerative diseases, and metabolic diseases, through its ability to stabilize its substrate proteins. Our group has utilized proteomic techniques to identify new potential substrate proteins for USP14, however, the underlying signaling pathways regulated by USP14 remain largely unknown. Here, we demonstrate the key role of USP14 in both heme metabolism and tumor invasion by stabilizing the protein BACH1. The cellular oxidative stress response factor NRF2 regulates antioxidant protein expression through binding to the antioxidant response element (ARE). BACH1 can compete with NRF2 for ARE binding, leading to the inhibition of the expression of antioxidant genes, including HMOX-1. Activated NRF2 also inhibits the degradation of BACH1, promoting cancer cell invasion and metastasis. Our findings showed a positive correlation between USP14 expression and NRF2 expression in various cancer tissues from the TCGA database and normal tissues from the GTEx database. Furthermore, activated NRF2 was found to increase USP14 expression in ovarian cancer (OV) cells. The overexpression of USP14 was observed to inhibit HMOX1 expression, while USP14 knockdown had the opposite effect, suggesting a role for USP14 in regulating heme metabolism. The depletion of BACH1 or inhibition of heme oxygenase 1 (coded by HMOX-1) was also found to significantly impair USP14-dependent OV cell invasion. In conclusion, our results highlight the importance of the NRF2-USP14-BACH1 axis in regulating OV cell invasion and heme metabolism, providing evidence for its potential as a therapeutic target in related diseases.

Epigenetic reactivation of PEG3 by EZH2 inhibitors suppresses renal clear cell carcinoma progress.

PEG3 is a paternally imprinted gene located on chromosome 19q13.4 and one of the most common low-expression genes in human ovarian cancer. PEG3 plays an important role in p53-related cell death. However, whether PEG3 plays a role in renal clear cell carcinoma (ccRCC) remains unclear. Here, we found that PEG3 was epigenetic inactivated and played a tumor suppressor role in ccRCC. Overexpression of PEG3 inhibited ccRCC cell proliferation and colony formation, while removal of PEG3 significantly promoted cell proliferation in vitro and tumor formation in nude mice in vivo. EZH2-mediated H3K27me3 at the PEG3 promoter suppressed PEG3 expression. EZH2 specific inhibitors promote PEG3 transcriptional expression through the transition from H3K27me3 to H3K27ac at the PEG3 promoter region. Depletion of PEG3 inhibited the activation of the p53 signaling pathway, resulting in the resistance of ccRCC to EZH2 inhibitors treatment. Thus, our data show that EZH2-mediated epigenetic inactivation of PEG3 promotes the progress of ccRCC, and reactivation of PEG3 may be a promising strategy for ccRCC.

Role of 18F-fluorodeoxyglucose PET/computed tomography in the diagnosis and treatment response assessment of primary bone lymphoma.

OBJECTIVE: Primary bone lymphoma (PBL) is a rare type of extranodal lymphoma, and the clinical application value of 18F-fluorodeoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) in PBL has not been fully evaluated. This study aimed to determine the imaging characteristics of PBL and investigate the value of 18 F-FDG PET/CT parameters. METHODS: A total of 25 patients with PBL who underwent PET/CT examination before treatment were included in this study. The clinicopathological parameters and PET/CT parameters were analyzed. RESULTS: Among the 25 patients, 7 patients had single lesions, 15 patients had nonsingle lesions (≥2) and 3 patients had diffuse distribution in the medullary cavity. The bone destruction types included osteolytic, osteogenic, normal density, mixed lytic and osteogenic. All patients showed increased FDG uptake, and the CT detection rate was 88%. Five patients underwent PET/CT assessment mid-treatment, and when assessed using the Deauville five-point scale, four patients were PET-negative and one patient was PET-positive. There were two PET-positive and three PET-negative patients when assessed using the Δ maximum standardized uptake value (SUV max ) method. Six patients underwent PET/CT imaging at the end of treatment. When assessed using the Deauville five-point scale, five patients (83%) were PET-negative and one patient (17%) was PET-positive. The same results were obtained when evaluated by the ΔSUV max method. CONCLUSION: PET/CT plays a substantial role in the diagnosis and treatment efficacy evaluation of PBL, and it should be recognized by clinicians and radiologists. Changes in metabolic parameters such as SUV, metabolic tumor volume and total lesion glycolysis have considerable potential for application in PBL diagnostics and treatment efficacy evaluation.

Safety of Left Subclavian Artery Selective Coverage without Revascularization in Thoracic Endovascular Aortic Repair for Type B Aortic Dissections.

PURPOSE: Whether to proceed left subclavian artery (LSA) revascularization in patients with LSA coverage due to insufficient proximal landing zone (PLZ) during thoracic endovascular aortic repair (TEVAR) remains controversial. METHODS: A total of 903 patients who received TEVAR were retrospectively analyzed. LSA could be covered if the PLZ was less than 15 mm accompanied with 1) a dominant or balanced right vertebral artery, 2) a complete circle of Willis, and 3) a left vertebral artery with a diameter ≥3 mm and without severe stenosis. RESULTS: LSA selective coverage was necessary for 35.0% (316/903) of the patients to extend the PLZ. Patients presented with weakness, pain, cooling and discoloration of the left upper extremity (LUE), and pulselessness of the left brachial artery were more in the LSA-covered group. The ischemia of LUE occurred more often in patients with LSA covered completely than in those with LSA covered partially. Functional arm status showed no significant difference in the arm, shoulder, and hand questionnaire scores at 12 months postoperative between the LSA-covered group and LSA-uncovered group, or between the LSA-covered completely group and LSA-covered partially group. CONCLUSION: It was safe to cover the LSA origin without revascularization if the PLZ was less than 15 mm accompanied with careful evaluation (description in method).

Lichong decoction reduces Matrix Metalloproteinases-2 expression but increases Tissue Inhibitors of Matrix Metalloproteinases-2 expression in a rat model of uterine leiomyoma.

OBJECTIVE: To study the effect of Lichong decoction (LD) on expression of matrix metalloproteinase- 2 (MMP-2) and metalloproteinase-2 (TIMP-2) in a rat model of uterine leiomyoma (UL). METHODS: UL was induced in rats using exogenous estrogen and progesterone. LD was administered (p.o.) for 4 weeks, and mifepristone (RU-486) used as a control. To observe the effect of LD on the uterine coefficient and uterine transverse diameter, a radioimmunoassay method was used to detect serum levels of sex hormones. Light microscopic analyses of pathologic changes in the tissues of UL rats were evaluated. Expression of the proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in uterine tissues was assessed by immunohistochemical staining and western blotting. RESULTS: A UL model in rats was established successfully. LD reduced uterine weight, uterine coefficient, and uterine transverse diameter compared with untreated controls. LD reduced levels of estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone in our UL models. LD improved the pathologic condition of uterine muscle. Expression of MMP-2 protein decreased to varying extents in LD-treated groups, but TIMP-2 levels were enhanced. LD appears to reduce MMP-2 expression and increase TIMP-2 expression in UL tissue. CONCLUSION: These data suggest that the mechanism of action of LD on ULs may involve reduction of MMP-2 expression and increase in TIMP-2 expression in rats.

Effect of Lichong decoction on expression of Bcl-2 and Bcl-2-associated X protein mRNAs in hysteromyoma model rat.

OBJECTIVE: To study on effects of Lichong decoction on expression of apoptosis-controlling genes, Bcl-2 and Bcl-2-associated X protein (Bax) mRNAs in hysteromyoma tissue of the hysteromyoma model rat. METHODS: Fifty Wistar female rats were randomly divided into a normal group, a model group, a Lichong decoction group, a Guizifuling capsule group and a Mifepristone group. The hysteromyoma rat model was established by intraperitoneal injection of exogenous estrin and progestogens. Pathological examination of uterine tissue, uterine coefficient and uterine transverse diameter were made under optic microscope and expressions of Bcl-2 and Bax mRNAs in uterine tissue in the groups were detected with real-time fluorescent quantitative polymerase chain reaction (PCR) technique. RESULTS: After treatment, under microscope it was found that in the Lichong decoction group myometrium thinned, muscle fiber slightly overgrowth or long and thin, regular arrangement, inserting phenomenon of inner circular muscle and external longitudinal muscle was occasionally or not seen in the Lichong decoction group. The uterine coefficient and the uterine transverse diameter significantly decreased (P < 0.01), and Bcl-2 mRNA expression significantly decreased (P < 0.01) and Bax mRNA expression significantly increased in hysteromyoma tissue (P < 0.01) in the Lichong decoction group as compared with the model group. CONCLUSION: Therapeutic effects of Lichong decoction on hysteromyoma is related with decrease of Bcl-2 mRNA expression and increase of Bax mRNA expression.

Effect of lichong decoction on expression of IGF-I and proliferating cell nuclear antigen mRNA in rat model of uterine leiomyoma.

OBJECTIVE: To study the effect of Lichong Decoction (Lichong Decoction for strengthening anti-pathogenic Qi and eliminating blood stasis) on the expression of insulin-like growth factor-I (IGF-I) and proliferating cell nuclear antigen (PCNA) mRNA in a rat model of uterine leiomyoma. METHODS: Fifty female Wistar rats were randomized into a normal control group, model group, Lichong Decoction group, Guizhifuling Capsule (Capsule containing Cassia Twig and Poria) group, and Mifepristone group. The uterine leiomyoma model was established by peritoneal injections of exogenous estrogen and progesterone hormone. The ultrastructural changes in cells of rat uterine tissues were observed with transmission electron microscopy, and the expression of IGF-I and PCNA mRNA was detected by real-time fluorescent quantitative PCR. RESULTS: Following treatment, cells in the Lichong Decoction group appeared to be arranged normally, the cellular morphology were almost in a normal state, hyperplasia and hypertrophy of the chondriosome was reduced, collagen fibers were arranged in a regular manner, without obvious hyperplasia, and the expression of IGF-I and PCNA mRNA was significantly decreased compared with the model group (P < 0.01). CONCLUSIONS: The effect of Lichong Decoction on uterine leiomyoma is related to its function in reducing the expression of IGF-I and PCNA mRNA.

Combined effects of serum trace metals and polymorphisms of CYP1A1 or GSTM1 on non-small cell lung cancer: a hospital based case-control study in China.

INTRODUCTION: The limited information for effects of serum trace elements and genetic polymorphisms on lung cancer is available. Based on a hospital based case-control study, the epidemiological questionnaires were completed by face to face interview, and the gene polymorphisms were tested by RFLP-PCR, and serum trace metals were measured by atomic absorption spectrophotometer, and the data was analyzed by the logistic regressive models. RESULTS: The high serum copper level (>1500 ng/ml) or serum copper/zinc ratio (>1) was the risk factors of NSCLC (OR=3.10, 11.03, respectively), but the ORs of the higher serum Zn (>1200 ng/ml), Se (>50 ng/ml) or Cr(3+) (>600 ng/ml) for NSCLC were all significantly less than 0.20 (all p<0.01) indicating strong protection against NSCLC. While the OR of CYP 1A1 variants carriers with a higher serum Cu or Cu/Zn ratio level was around 3.38 and 12.59, respectively, the risk of CYP1A1 variants carriers with a higher serum Zn is 0.18, Se 0.04 or Cr(3+) 0.28. Similarly, compared with the carriers of GSTM1 power with a lower serum Zn, Se or Cr(3+), the OR of the carriers of GSTM1 null with a higher serum Zn, Se and Cr(3+) was separately 0.16, 0.07 and 0.26, highlighting the protection against NSCLC. CONCLUSIONS: Our findings suggested that CYP1A1 or GSTM1 variants may significantly modify the associations between level of serum trace metals (Cu, Zn, Se or Cr) and NSCLC, indicating the intriguing pathogenesis of lung cancer.

[Research progress on epigenetics of lung cancer].

Epigenetic events, a key driving force in the development of lung cancer, two changes integral to epigenetic transcriptional control are DNA methylation and covalent modification of histone proteins. Aberrant methylation may be the most common mechanism of inactivating cancer-related genes in lung cancer, and histone modification may be closely associated with DNA methylation. It was seemed that epigenetic changes could be of the earliest events observed during cancer development, making them excellent targets for chemoprevention. Understanding the mechanisms involved in epigenetic regulation and how they interact with genetic changes during lung cancer progression could facilitate development of newer, more efficacious, and safer chemopreventive agents.