Roles of circRNAs in regulating the tumor microenvironment.

CircRNAs, a type of non-coding RNA widely present in eukaryotic cells, have emerged as a prominent focus in tumor research. However, the functions of most circRNAs remain largely unexplored. Known circRNAs exert their regulatory roles through various mechanisms, including acting as microRNA sponges, binding to RNA-binding proteins, and functioning as transcription factors to modulate protein translation and coding. Tumor growth is not solely driven by gene mutations but also influenced by diverse constituent cells and growth factors within the tumor microenvironment (TME). As crucial regulators within the TME, circRNAs are involved in governing tumor growth and metastasis. This review highlights the role of circRNAs in regulating angiogenesis, matrix remodeling, and immunosuppression within the TME. Additionally, we discuss current research on hypoxia-induced circRNAs production and commensal microorganisms' impact on the TME to elucidate how circRNAs influence tumor growth while emphasizing the significance of modulating the TME.

The Emerging Roles and Mechanisms of PAQR3 in Human Cancer: Pathophysiology and Therapeutic Implications.

Cancer was one of the common causes of death in the world, and it was increasing year by year. At present, Progestin and AdipoQ receptor family member 3 (PAQR3) was widely studied in cancer. It has been found that PAQR3 was down regulated in various cancers, such as the gastric cancer, osteosarcoma, glioma, hepatocellular carcinoma, acute lymphoblastic leukemia, laryngeal squamous cell carcinoma, esophageal cancer, breast cancer, non-small cell lung cancer, and colorectal cancer. The decreased expression of PAQR3 was associated with short overall survival and disease-free survival in patients with gastric cancer, hepatocellular carcinoma, laryngeal squamous cell carcinoma, esophageal cancer, breast cancer, and non-small cell lung cancer. PAQR3 could inhibit cancer progression by using the Ras/Raf/MEK/ERK, PI3/AKT, EMT and other mechanisms, and was negatively regulated by the miR-543, miR-15b-5p and miR-15b. The roles and signaling mechanisms of PAQR3, and the relationship between the expression of PAQR3 and prognosis in cancer progression are reviewed in this article, and provides new tumor marker and idea to guide cancer treatment.

Overexpression of TWF1 promotes lung adenocarcinoma progression and is associated with poor prognosis in cancer patients through the MMP1 signaling pathway.

Background: It has been reported that twinfilin actin binding protein 1 (TWF1) is associated with the progression of breast and pancreatic cancers. However, the roles and mechanisms of TWF1 in lung adenocarcinoma (LUAD) have not been reported. Methods: The expression levels of TWF1 in LUAD and normal tissues were analyzed using The Cancer Genome Atlas (TCGA) database, and validation was carried out with 12 clinical samples. The relationship between TWF1 expression and LUAD patients' clinical indices and immunity was investigated. Cell Counting Kit-8 (CCK-8) and migration and invasion assays were employed to explore the effects of downregulated TWF1 on LUAD cell proliferation and metastasis. Results: TWF1 was upregulated in LUAD tissues, and upregulated TWF1 was correlated with the tumor (T) stage, node (N) stage, clinical classification, overall survival (OS), and progression-free interval (PFI) of LUAD patients. Moreover, the Cox regression analysis showed that TWF1 overexpression was an independent risk factor for the poor prognosis of LUAD patients. TWF1 expression was associated with tumor immune infiltration (such as dendritic cells resting, eosinophils, macrophages M0, and others), drug sensitivity (such as A-770041, Bleomycin, and BEZ235), tumor mutation burden (TMB), and sensitivity to immunotherapy. In the cell model, TWF1 expression interference significantly prohibited LUAD cell proliferation, migration, and invasion, which might be relevant to aberrant MMP1 protein downregulation. Conclusions: TWF1 overexpression was correlated with poor prognoses and immune status of LUAD patients. Inhibited TWF1 expression delayed the growth and migration of cancer cells by downregulating MMP protein, implying that TWF1 is a promising biomarker for the prognoses of LUAD patients.

A new prognostic model for RHOV, ABCC2, and CYP4B1 to predict the prognosis and association with immune infiltration of lung adenocarcinoma.

Background: Lymph node metastasis is one of the important factors affecting the prognosis of lung adenocarcinoma (LUAD) patients. The key molecules in lymph node metastasis have not yet been fully revealed. Therefore, we aimed to construct a prognostic model based on lymph node metastasis-related genes to evaluate the prognosis of LUAD patients. Methods: The differentially expressed genes (DEGs) in the process of LUAD metastasis were identified in The Cancer Genome Atlas (TCGA) database, and the biological roles of the DEGs were depicted using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and a protein-protein interaction (PPI) network. Survival analysis and Cox regression analysis were used to identify the genes related to the prognosis of patients with LUAD, and a nomogram and a prognostic model were constructed. The potential prognostic value, immune escape, and regulatory mechanisms of the prognostic model in LUAD progression were explored through survival analysis and gene set enrichment analysis (GSEA). Results: A total of 75 genes were upregulated, and 138 genes were downregulated in tissues of lymph node metastasis. The expression levels of STC1, CYP17A1, RHOV, GUCA2B, TM4SF20, DEFB1, CRHR2, ABCC2, CYP4B1, KRT16, and NTS were revealed as risk factors for a poor prognosis in LUAD patients. High-risk LUAD patients had a poor prognosis in the prognostic model based on RHOV, ABCC2, and CYP4B1. The clinical stage and the risk score were found to be independent risk factors for a poor prognosis in LUAD patients, and the risk score was associated with the tumor purity, T cell, natural killer (NK) cell, and other immune cells. The prognostic model might affect the progression of LUAD using DNA replication, the cell cycle, P53, and other signaling pathways. Conclusions: Lymph node metastasis-related genes RHOV, ABCC2, and CYP4B1 are associated with a poor prognosis in LUAD. A prognostic model based on RHOV, ABCC2, and CYP4B1 might predict the prognosis of LUAD patients and be associated with immune infiltration.

Characterization of fatty acid metabolism-related lncRNAs in lung adenocarcinoma identifying potential novel prognostic targets.

Lung adenocarcinoma (LUAD), a malignant respiratory tumor with an extremely poor prognosis, has troubled the medical community all over the world. According to recent studies, fatty acid metabolism (FAM) and long non-coding RNAs (lncRNAs) regulation have shown exciting results in tumor therapy. In this study, the original LUAD patient data was obtained from the TCGA database, and 12 FAM-related lncRNAs (AL390755.1, AC105020.6, TMPO-AS1, AC016737.2, AC127070.2, LINC01281, AL589986.2, GAS6-DT, AC078993.1, LINC02198, AC007032.1, and AL021026.1) that were highly related to the progression of LUAD were finally identified through bioinformatics analysis, and a risk score model for clinical reference was constructed. The window explores the immunology and molecular mechanism of LUAD, aiming to shed the hoping light on LUAD treatment.

Ectopic adrenocorticotrophic hormone syndrome initially presenting as abnormal mental behavior caused by thymic carcinoid: a case report.

Background: Thymic carcinoid is a rare highly differentiated neuroendocrine neoplasm, which can manifest as endocrine disorders caused by ectopic adrenocorticotrophic hormone (ACTH) syndrome. Although clinical manifestations such as hypertension and hypokalemia are common manifestations in patients with ectopic ACTH syndrome, clinicians should also be aware of the mental and behavioral abnormalities that may initially appear in patients. It is extremely rare for patients with ectopic ACTH syndrome caused by thymic carcinoid to concurrently exhibit abnormal mental behavior, especially as the initial clinical manifestation of the tumor. Studies have suggested that abnormal mental behavior may be related to elevated blood cortisol levels. Case Description: A patient was admitted to hospital due to abnormal mental behavior, manifesting as hyperphasia involving gibberish and illogical language, trance, and a state of suspicion. The patient had experienced persecutory delusion. Auxiliary examination revealed elevated cortisol and ACTH. Chest computed tomography (CT) showed right anterior mediastinal tumor. After discussion, the multi-disciplinary team (MDT) concluded that ectopic ACTH syndrome derived from the thymus should be considered. After excluding surgical contraindications, a thymic tumor was resected, and the postoperative pathology confirmed that it was thymic carcinoid. At 6 postoperative months, the results were as follows: cortisol at 8:00 am 196.50 nmol/L; and ACTH at 8:00 am 28.63 pg/mL. The patient's mental behavior had returned to normal, and normal communication was possible. The postoperative symptoms and signs of the patient were improved, which reiterated the presence ectopic ACTH syndrome caused by thymic carcinoid. Conclusions: Thymic carcinoid with ectopic ACTH syndrome is very rare in clinical practice, and it is easily missed and misdiagnosed. Although clinical manifestations such as hypertension and hypokalemia are common manifestations in patients with Cushing's syndrome, clinicians should be aware that patients with Cushing's syndrome may initially exhibit abnormal mental behavior. Clinically, if the patient exhibits abnormal mental behavior accompanied by symptoms such as hypokalemia, hypertension, and diabetes, blood cortisol and ACTH hormone levels should be screened without delay. If the levels are found to be significantly increased, ACTH syndrome should be highly suspected.

Sintilimab plus chemotherapy achieved symptom relief in stage IV lung squamous cell carcinoma with superior vena cava syndrome: a case report.

Lung cancer is the second most common and mortality disease in the world. Most patients with lung cancer are already at the advanced stage when diagnosed. There are multiple treatments for advanced lung cancer. Among them, immunotherapy plus chemotherapy has gradually become the first-line treatment. Lung cancer has multiple complications, superior vena cava syndrome (SVCS) is a common complication of patients with advanced lung cancer. The current treatments include radiotherapy, chemotherapy, and stent implantation. Stent implantation has the disadvantages of invasiveness and poor efficacy. Immunotherapy, as an emerging treatment for tumors, has shown significant advantages in treating patients with advanced lung cancer. However, the treatment of advanced lung cancer with SVCS using immunotherapy has rarely been reported. Here, we reported a 48-year-old male patient with stage IV (T4N3M1) lung squamous cell carcinoma. After receiving 1 cycle (3 weeks) of comprehensive treatment with sintilimab plus chemotherapy, the tumor mass shrank by 30% to achieve partial response (PR), collateral circulation was formed, and most of the symptoms caused by SVCS disappeared. After 3 cycles of treatment, the tumor shrank by nearly 90%, and the superior and inferior vena cava opened larger than before. Our case provides a novel treatment strategy for such patients.

Diagnosis and treatment of pericardial mesothelioma by mediastinal mass resection: a case report.

Background: Pericardial mesothelioma (PeM) is a rare disease with non-specific symptoms at the onset, because of its rarity, the relevant literature is limited to case reports and small case series, with no cases exceeding 100 in more than 20 years. As the most common initial symptoms are chest tightness and shortness of breath, early diagnosis is difficult, and the beginning of treatment is easily delayed. We present a rare case of difficult-to-diagnose PeM in which the diagnosis was clarified by surgery and the patient achieved a long survival, providing clinicians with our experience in treating this disease at an early stage of diagnosis and early treatment. Case Description: A 65-year-old female patient attended Affiliated Hospital of Zunyi Medical University, complaining about chest tightness and shortness of breath after activity for the last 2 months, accompanied by edema of the lower limbs in last month. A well circumscribed anterior-mediastinal, partially cystic mass was observed on the chest computed tomography. The patient's heart was compressed by the mass, and the patient had cardiac tamponade symptoms. Cardiac ultrasound showed the enlargement of the right heart, a widened pulmonary artery, pulmonary hypertension, and severe tricuspid regurgitation. The nature of the mass could not be determined prior to the surgery. Anterior superior mediastinal tumour resection and partial pericardial resection and closed thoracic drainage in a median open chest were performed, and pathohistological analysis revealed localized pericardial, epithelioid mesothelioma. In a follow-up after 19 months patient was generally well and without specific discomfort. Conclusions: Differential diagnosis of the anterior mediastinal mass is broad. In patients with a mediastinal tumour who have significant symptoms, are difficult to diagnose and can tolerate surgery, the thoracic surgeon can use surgery as early as possible to make a definitive diagnosis, save the patient's life, and/or improve the patient's quality of life, experienced pathologist is essential to make fast and correct diagnosis.

Screening and evaluation of the role of immune genes of brain metastasis in lung adenocarcinoma progression based on the TCGA and GEO databases.

BACKGROUND: Brain metastasis was one of the factors leading to the poor long-term prognosis of patients with lung adenocarcinoma (LUAD). METHODS: The expression levels of immune genes in LUAD and LUAD brain metastases tissues were analyzed in GSE161116 dataset using the GEO2R, and the levels of differential immune genes in normal lung and LUAD tissues were verified. The biological functions and signaling mechanisms of the differential immune genes were explored via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Cox regression analysis was used to screen the prognostic factors of LUAD patients, and a risk model was constructed. The role of the model was checked in the development of LUAD via receiver operating characteristic analysis, gene set enrichment analysis, and Cox regression analysis. RESULTS: Differentially expressed genes (DEGs) in brain metastasis were involved in the adaptive immune response, B cell differentiation, leukocyte migration, NF-kB signaling pathway, among others. The expression levels of TNFRSF11A, MS4A2, IL11, CAMP, MS4A1, and F2RL1 were independent factors affecting the poor prognosis of LUAD patients via Cox regression analysis and Akaike information criterion. In the constructed risk model, the overall survival of LUAD patients in the high-risk group was poor. The risk model was significantly related to the gender, clinical stage, T stage, lymph node metastasis, and survival status of LUAD patients. In addition, the risk model score was an independent risk factor that affected the poor prognosis of LUAD patients. TNFRSF11A, CAMP, F2RL1, IL11, MS4A1, and MS4A2 of the risk factors had diagnostic significance in LUAD brain metastasis and LUAD. The risk model participated in cytokinetic process, cell cycle, citrate cycle TCA cycle, etc. The risk model score was correlated with the levels of B cells memory, mast cells resting, macrophages M0, mast cells activated, neutrophils, eosinophils, T cells gamma delta, and immune cell markers. CONCLUSIONS: The risk model based on the LUAD brain metastasis immune factors TNFRSF11A, MS4A2, IL11, CAMP, MS4A1, and F2RL1 was related to the diagnosis, poor prognosis, and immune infiltrating cells of LUAD patients, and is expected to provide a reference for the development of treatment strategies for LUAD patients.

Porcupine inhibitor LGK­974 inhibits Wnt/ß­catenin signaling and modifies tumor­associated macrophages resulting in inhibition of the malignant behaviors of non­small cell lung cancer cells.

Tumor­associated macrophages (TAMs) are critical components of the tumor microenvironment that are tightly associated with malignancies in human cancers, including lung cancer. LGK­974, a small molecular inhibitor of Wnt secretion, was reported to block Wnt/ß­catenin signaling and exert anti­inflammatory effects by suppressing pro­inflammatory gene expression in cancer cells. Although it was reported that Wnt/ß­catenin was critical in regulating TAMs, it is still largely unknown whether LGK­974 regulates tumor malignancies by regulating TAMs. The present study firstly verified that the polarization of TAMs was regulated by LGK­974. LGK­974 increased M1 macrophage functional markers and decreased M2 macrophage functional markers. The addition of Wnt3a and Wnt5a, two canonical Wnt signaling inducers, reversed the decrease in M1 macrophage functional markers, including mannose receptor, IL­10 and Arg1, by activating Wnt/ß­catenin signaling. Conditioned medium from LGK­974­modified TAMs inhibited the malignant behaviors in A549 and H1299 cells, including proliferation, colony formation and invasion, by blocking Wnt/ß­catenin signaling. LGK­974­modified TAMs blocked the cell cycle at the G1/G0 phase, which was reversed by the addition of Wnt3a/5a, indicating that LGK­974 regulates the microenvironment by blocking Wnt/ß­catenin signaling. Taken together, the results indicate that LGK­974 indirectly inhibited the malignant behaviors of A549 and H1299 cells by regulating the inflammatory microenvironment by inhibiting Wnt/ß­catenin signaling in TAMs.

Evaluation of clinical value and potential mechanism of MTFR2 in lung adenocarcinoma via bioinformatics.

BACKGROUND: Mitochondrial fission regulator 2 (MTFR2) was involved in the progression and development of various cancers. However, the relationship between MTFR2 with lung adenocarcinoma (LUAD) had not been reported. Herein, this study analyzed the clinical significance and potential mechanisms of MTFR2 in LUAD via bioinformatics tools. RESULTS: We found that the level of MTFR2 was increased, and correlated with sex, age, smoking history, neoplasm staging, histological subtype and TP53 mutation status in LUAD patients. Kaplan-Meier survival analysis showed LUAD patients with increased MTFR2 had a poor prognosis. In addition, univariate COX regression analysis showed neoplasm staging, T stage, distant metastasis and MTFR2 level were risk factors for the prognosis of LUAD. A total of 1127 genes were coexpressed with MTFR2, including 840 positive and 208 negative related genes. KEGG and GSEA found that MTFR2 participated in the progression of LUAD by affecting cell cycle, DNA replication, homologous recombination, p53 signaling pathway and other mechanisms. The top 10 coexpressed genes, namely CDK1, CDC20, CCNB1, PLK1, CCNA2, AURKB, CCNB2, BUB1B, MAD2L1 and BUB1 were highly expressed, and were associated with poor prognosis in LUAD. CONCLUSIONS: Consequently, we elucidated MTFR2 was a biomarker for diagnosis and poor prognosis in LUAD, and might participate in the progression of LUAD via affecting cell cycle, DNA replication, homologous recombination and p53 signaling pathway.

Thoracic endometriosis: a case report and review of the literature.

Thoracic endometriosis is characterized by the presence of normal functioning endometrial tissues in normal pleural, diaphragm, or lung parenchyma, and main clinical symptoms include pneumothorax, menstrual hemothorax, menstrual hemoptysis, and pulmonary nodules. Chest X-ray (CXR), computed tomography (CT), magnetic resonance imaging (MRI), bronchoscopy, and surgical biopsy could be applied to the diagnosis of TE. Both drug therapy and surgical treatment were widely used to treat this disease, but no theory was used to guide the choice of treatment options. This paper introduces a case of menstrual hemoptysis due to endometriosis, and the final surgical treatment was chosen. The patient recovered well postoperatively and reported no hemoptysis during 2 months of follow-up. Reexamination of the chest through CT showed no ground-glass lesions or pulmonary exudative lesions. We make the following recommendations for patient selection when considering a surgical approach to the treatment of TE. Patients for whom surgery should be considered are those who (I) do not respond to drug therapy or relapse once drug therapy is withdrawn, (II) cannot tolerate drug therapy or who may wish to get pregnant in the near future (III) have limited lesions which are able to be completely removed during surgery. Patients in whom surgery is not recommended include those who have extensive lesions which cannot be surgically removed, including those with diaphragm or pleural involvement as the diseased tissues must be completely removed to avoid recurrence, and those who are unfit for surgery.

Compression of superior vena cava and azygos vein by a giant mediastinal mature cystic teratoma: a case report.

Teratoma is a common type of mediastinal tumor, often located in the anterior mediastinum. Mediastinal teratomas often occur in young and middle-aged people, and account for 5-21.5% of mediastinal tumors. Mature cystic teratoma is a common type of mediastinal teratoma, its onset is slow, and most patients are asymptomatic. In a few patients, the tissue around the mediastinum is invaded or there is malignant transformation, which results in chest pain, chest tightness, a cough, and other symptoms. In this case, the patient had a giant teratoma, compressing large blood vessels and nerves, complicated by pleural and pericardial effusion. The 21-year-old female patient was misdiagnosed with tuberculous disease because of chronic cough and expectoration. Her initial symptoms improved after anti-tuberculosis treatment; however, an imaging examination showed that the lesion had enlarged some 9 months later. Surgery was performed at our hospital, as the tumor was squeezing blood vessels, and the trachea was seriously adhering to the surrounding tissue. To avoid damage to the peripheral blood vessels and nerves, many residual tissues were retained after the operation. The post-operative pathology results confirmed that the patient had a mature mediastinal cystic teratoma. One year after the operation, there was no recurrence, the peripheral blood vessels had basically returned, and the patient did not have any nerve injury. Effusion caused by mediastinal teratoma should be carefully differentiated from tuberculous diseases to avoid unnecessary damage to patients during treatment. Separation can be difficult in benign mediastinal tumors with severe adhesion. To avoid the trauma caused by the excessive separation of a tumor, it is our view that part of the residual tissue should be retained and left to be absorbed naturally.

PAQR3 Inhibits Non-small Cell Lung Cancer Growth by Regulating the NF-κB/p53/Bax Axis.

BACKGROUND: The expression of progestin and adipoQ receptor 3 (PAQR3) is generally downregulated in multiple tumors, which is associated with tumor progression and poor prognosis. METHODS: The clinical value of PAQR3 was analyzed using various databases and in 60 patients with non-small cell lung cancer (NSCLC). In addition, cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the effect of PAQR3 on the growth of NSCLC cells in vitro. Gene set enrichment analysis (GSEA) was performed to investigate the possible mechanism through which PAQR3 is involved in the progression of lung cancer. Furthermore, western blotting was employed to verify the relevant mechanism. RESULTS: The expression of PAQR3 was decreased in 60 NSCLC patients and was related to the histological subtype, lymph node metastasis, tumor size, and diagnosis of NSCLC. Patients with lung adenocarcinoma with increased PAQR3 expression tended to have a better prognosis. Besides, PAQR3 inhibited proliferation, clone formation, and cycle transition in NSCLC cells, but induced apoptosis. The results of GSEA showed that PAQR3 regulated the progression of lung cancer by affecting cell cycle, DNA replication, and the p53 signaling pathway. We confirmed that PAQR3 overexpression inhibited the expression of NF-κB, while it increased the expression of p53, phospho-p53, and Bax. On the contrary, PAQR3 inhibition played an opposite role in these proteins. CONCLUSION: PAQR3 inhibited the growth of NSCLC cells through the NF-κB/P53/Bax signaling pathway and might be a new target for diagnosis and treatment.

High BANCR expression is associated with worse prognosis in human malignant carcinomas: an updated systematic review and meta-analysis.

BACKGROUND: BRAF-activated noncoding RNA (BANCR) is aberrantly expressed in various tumor tissues and has been confirmed to function as a tumor suppressor or oncogene in many types of cancers. Considering the conflicting results and insufficient sampling, a meta-analysis was performed to explore the prognostic value of BANCR in various carcinomas. METHODS: A comprehensive literature search of PubMed, Web of Science, EMBASE, Cochrane Library and the China National Knowledge Infrastructure (CNKI) was conducted to collect relevant articles. RESULTS: The pooled results showed a strong relationship between high BANCR expression and poor overall survival (OS) (HR (hazard ratio) =1.60, 95% confidence interval (CI): 1.19-2.15, P = 0.002) and recurrence-free survival (RFS) (HR = 1.53, 95% CI: 1.27-1.85, P < 0.00001). In addition, high BANCR expression predicted advanced tumor stage (OR (odds ratio) =2.39, 95% CI: 1.26-4.53, P = 0.008), presence of lymph node metastasis (OR = 2.03, 95% CI: 1.08-3.83, P = 0.03), positive distant metastasis (OR = 3.08, 95% CI: 1.92-4.96, P < 0.00001) and larger tumor sizes (OR = 1.63, 95% CI: 1.09-2.46, P = 0.02). However, no associations were found for smoking status (OR = 1.01, 95% CI: 0.65-1.56, P = 0.98), age (OR = 0.88, 95% CI: 0.71-1.09, P = 0.236) and sex (OR = 0.91, 95% CI: 0.72-1.16, P = 0.469). The sensitivity analysis of OS showed that the results of each publication were almost consistent with the combined results, and the merged results have high robustness and reliability. CONCLUSIONS: The results showed that elevated BANCR expression was associated with unfavorable prognosis for most cancer patients, and BANCR could serve as a promising therapeutic target and independent prognostic predictor in most of cancer types.

Mitochondria-associated protein LRPPRC exerts cardioprotective effects against doxorubicin-induced toxicity, potentially via inhibition of ROS accumulation.

Doxorubicin (DOX) has been widely employed to treat cancer, particularly solid tumors and hematological malignancies, owing to its high efficacy; however, chemotherapy has been indicated to be cardiotoxic and induce adverse effects, including mitochondrial dysfunction and DNA damage, which limits its application. The mitochondria-associated protein leucine-rich pentatricopeptide repeat-containing (LRPPRC) has been reported to serve critical regulatory roles in physiological processes via regulating mitochondrial function. The aim of the present study was to investigate the possible protective effects of LRPPRC against DOX-induced cardiac injury. In a DOX-induced cardiotoxicity model in H9C2 cells, LRPPRC was indicated to be transcriptionally upregulated and stabilize Bcl-2 and Bax. LRPPRC overexpression exhibited protective effects against proliferation and both apoptotic and non-apoptotic cell death following DOX treatment, but not under normal conditions. It was additionally observed that overexpressed LRPPRC reversed the decreases in ATP synthesis, mitochondrial mass and transcriptional activity, which were induced by DOX exposure. Overexpressed LRPPRC also decreased the accumulation of reactive oxygen species (ROS) under DOX treatment and inhibited cell death to a similar extent as N-acetyl-L-cysteine, which is a known ROS scavenger, indicating that LRPPRC potentially exerts protective effects via inhibiting ROS accumulation. Moreover, LRPPRC overexpression protected H9C2 cells against oxidative stress induced by H2O2, which also indicated its ROS-scavenging function. The present study demonstrated for the first time, to the best of our knowledge, that DOX-induced LRPPRC may exert cardioprotective effects via inhibiting ROS accumulation, thereby maintaining mitochondrial function.

miR-410 induces both epithelial-mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer.

Radiotherapy remains one of the major treatments for non-small cell lung cancer (NSCLC) patients; whereas intrinsic or acquired radioresistance limits its efficacy. Nevertheless, most studies so far have only focused on acquired resistance. The exact mechanisms of intrinsic radioresistance in NSCLC are still unclear. A few studies have suggested that epithelial-mesenchymal transition (EMT) is associated with radioresistance in NSCLC. However, little is known about whether the abnormal expression of specific microRNAs induces both EMT and radioresistance. We previously found that miR-410 has multiple roles as an oncomiRNA in NSCLC. In this study, we revealed that miR-410 overexpression promoted EMT and radioresistance, accompanied by enhanced DNA damage repair both in vitro and in vivo. Conversely, knockdown of miR-410 showed the opposite effects. We further demonstrated that PTEN was a direct target of miR-410 by using bioinformatic tools and dual-luciferase reporter assays, and the miR-410-induced EMT and radioresistance were reversed by PI3K, Akt, and mTOR inhibitors or by restoring the expression of PTEN in NSCLC cells. In addition, we preliminarily found that the expression of miR-410 was positively correlated with EMT and negatively associated with the expression of PTEN in NSCLC specimens. In summary, these results demonstrated that miR-410 is an important regulator on enhancing both NSCLC EMT and radioresistance by targeting the PTEN/PI3K/mTOR axis. The findings suggest that miR-410-induced EMT might significantly contribute to the enhanced radioresistance. Therefore, miR-410 may serve as a potential biomarker or therapeutic target for NSCLC radiotherapy.

Glycyrrhizic acid exerts protective effects against hypoxia/reoxygenation-induced human coronary artery endothelial cell damage by regulating mitochondria.

Hypoxia/reoxygenation (H/R) is one of the main causes of coronary artery disease (CAD), which is primarily induced by damage to coronary artery endothelial cells (CAECs). Glycyrrhizic acid (GA) is a natural and abundant pentacyclic triterpenoid glycoside of the licorice root extract, and it has been reported to elicit protective effects against hypoxia, inflammation and apoptosis in ischemic myocardium; therefore, GA may serve as a promising therapeutic agent for ischemia-associated CAD. In the present study, the protective effects of GA against H/R-induced injury in CAECs were investigated. Treatment with GA during H/R maintained cell viability and decreased H/R-induced cell apoptosis in human CAECs. In addition, H/R-mediated induction of intracellular and mitochondrial reactive oxygen species (ROS) was significantly decreased by GA exposure. Similar to ROS scavengers, GA treatment not only exhibited protective effects, but also maintained the mitochondrial membrane potential after H/R and inhibited H/R-induced mitochondrial dysfunction, including deficits in ATP synthesis, mitochondrial DNA copy number and mitochondrial transcriptional activity. Furthermore, GA decreased autophagy/mitophagy, and its protective effect against H/R was abolished by autophagy promotion. Collectively, the results suggested that GA exhibited protective effects against H/R-induced CAEC injury by decreasing ROS accumulation and maintaining mitochondrial homeostasis. Further investigation into the precise mechanisms underlying the decrease in ROS accumulation induced by GA is required.

Evaluation of the Prognostic Value of STEAP1 in Lung Adenocarcinoma and Insights Into Its Potential Molecular Pathways via Bioinformatic Analysis.

BACKGROUND: Upregulation of the six-transmembrane epithelial antigen of prostate-1 (STEAP1) is closely associated with prognosis of numerous malignant cancers. However, its role in lung adenocarcinoma (LUAD), the most common type of lung cancer, remains unknown. This study aimed to investigate the role of STEAP1 in the occurrence and progression of LUAD and the potential mechanisms underlying its regulatory effects. METHODS: STEAP1 mRNA and protein expression were analyzed in 40 LUAD patients via real-time PCR and western blotting, respectively. We accessed the clinical data of 522 LUAD patients from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) to investigate the expression and prognostic role of STEAP1 in LUAD. Further, we performed gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) to elucidate the potential mechanism underlying the role of STEAP1 in LUAD. The protein-protein interaction (PPI) network of STEAP1 was analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and hub genes with significant positive and negative associations with STEAP1 were identified and their role in LUAD prognosis was predicted. RESULTS: STEAP1 was significantly upregulated in LUAD patients and associated with LUAD prognosis. Further, TCGA data indicated that STEAP1 upregulation is correlated with the clinical prognosis of LUAD. GO and KEGG analysis revealed that the genes co-expressed with STEAP1 were primarily involved in cell division, DNA replication, cell cycle, apoptosis, cytokine signaling, NF-kB signaling, and TNF signaling. GSEA revealed that homologous recombination, p53 signaling pathway, cell cycle, DNA replication, apoptosis, and toll-like receptor signaling were highly enriched upon STEAP1 upregulation. Gene Expression Profiling Interactive Analysis (GEPIA) analysis revealed that the top 10 hub genes associated with STEAP1 expression were also associated with the LUAD prognosis. CONCLUSION: STEAP1 upregulation potentially influences the occurrence and progression of LUAD and its co-expressed genes via regulation of homologous recombination, p53 signaling, cell cycle, DNA replication, and apoptosis. STEAP1 is a potential prognostic biomarker for LUAD.

Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells.

Macrophages are a heterogeneous group of phagocytes that play critical roles in inflammation, infection and tumor growth. Macrophages respond to different environmental factors and are thereby polarized into specialized functional subsets. Although hypoxia is an important environmental factor, its impact on human macrophage polarization and subsequent modification of the inflammatory microenvironment have not been fully established. The present study aimed to elucidate the effect of hypoxia exposure on the ability of human macrophages to polarize into the classically activated (pro-inflammatory) M1, and the alternatively activated (anti-inflammatory) M2 phenotypes. The effect on the inflammatory microenvironment and the subsequent modification of A549 lung carcinoma cells was also investigated. The presented data show that hypoxia promoted macrophage polarization towards the M2 phenotype, and modified the inflammatory microenvironment by decreasing the release of proinflammatory cytokines. Modification of the microenvironment by proinflammatory M1 macrophages under hypoxia reversed the inhibition of malignant behaviors within the proinflammatory microenvironment. Furthermore, it was identified p38 signaling (a major contributor to the response to reactive oxygen species generated by hypoxic stress), but not hypoxia-induced factor, as a key regulator of macrophages under hypoxia. Taken together, the data suggest that hypoxia affects the inflammatory microenvironment by modifying the polarization of macrophages, and thus, reversing the inhibitory effects of a proinflammatory microenvironment on the malignant behaviors of several types of cancer cell.