HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.

Elevated serum levels of leukocyte cell-derived chemotaxin 2 are associated with the prevalence of metabolic syndrome.

AIMS: Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice. METHODS: Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice. RESULTS: Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36-17.14] vs. 3.74[2.61-5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson's correlation analysis showed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01-2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68-0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice. CONCLUSIONS: Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS.

CD4+ T-Cell Legumain Deficiency Attenuates Hypertensive Damage via Preservation of TRAF6.

BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmnf/f/CD4Cre), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmnf/f/Foxp3YFP Cre), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.

HMGB family proteins: Potential biomarkers and mechanistic factors in cardiovascular diseases.

Cardiovascular disease (CVD) is the most fatal disease that causes sudden death, and inflammation contributes substantially to its occurrence and progression. The prevalence of CVD increases as the population ages, and the pathophysiology is complex. Anti-inflammatory and immunological modulation are the potential methods for CVD prevention and treatment. High-Mobility Group (HMG) chromosomal proteins are one of the most abundant nuclear nonhistone proteins which act as inflammatory mediators in DNA replication, transcription, and repair by producing cytokines and serving as damage-associated molecular patterns in inflammatory responses. The most common and well-studied HMG proteins are those with an HMGB domain, which participate in a variety of biological processes. HMGB1 and HMGB2 were the first members of the HMGB family to be identified and are present in all investigated eukaryotes. Our review is primarily concerned with the involvement of HMGB1 and HMGB2 in CVD. The purpose of this review is to provide a theoretical framework for diagnosing and treating CVD by discussing the structure and function of HMGB1 and HMGB2.

Overexpression of FADD and Bcl-XS proteins as novel prognostic biomarkers for surgically resected non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most widespread cancer with increasing morbidity and mortality. FAS-associated protein with death domain (FADD) is considered as an essential instrument in cell death, whereas Bcl-XS promotes apoptosis through inhibiting the activity of Bcl-2 and Bcl-XL. OBJECTIVE AND METHODS: We detected the expression of FADD and Bcl-XS in resected NSCLC tissues by immunohistochemistry, and investigated their association with clinicopathological characteristics and prognostic significance of NSCLC patients. RESULTS: Bcl-XS expression was significantly increased in well and moderate differentiated lung SCC (P= 0.004). Lung ADC patients with overexpression of FADD and lung SCC patients with low expression of Bcl-XS had importantly lower overall survival rates by Kaplan-Meier analysis (P= 0.033, P= 0.02, respectively). Multivariate analysis confirmed that elevated expression of FADD was an independent poor prognostic factor for patients with surgically resected lung ADC (P= 0.027) and increased expression of Bcl-XS was an independent good prognostic factor for patients with surgically resected lung SCC (P= 0.016)CONCLUSION: Elevated expression of FADD was identified as independent poor prognostic factor for patients with surgically resected lung ADC, however, increased expression of Bcl-XS was an independent good prognostic biomarker for patients with surgically resected lung SCC.

Clinical significance of PD-L1 expression in patients with surgically resected non-small cell lung cancer. / PD-L1在非小细胞肺癌中表达的临床意义.

OBJECTIVES: To explore the expression of programmed death ligand-1 (PD-L1) as well as the correlation between the expression and the clinicopathological features or prognosis in non-small cell lung cancer (NSCLC). METHODS: The expression of PD-L1 protein in 254 cases of surgically resected lung adenocarcinoma (L-ADC), 228 cases of surgically resected lung squamous cell cancer (L-SCC), and 99 cases of non-cancerous control lung tissues was detected with immunohistochemical SP method. The correlation between the PD-L1 expression and clinicopathological features was analyzed. Kaplan-Meier univariate and Cox multivariate regression analyses were performed to assess the prognosis of patients with L-ADC and L-SCC, respectively. RESULTS: Positive percentage of PD-L1 protein expression was higher in the tissues of L-ADC and L-SCC than that in the non-cancerous control lung tissues respectively (both P<0.05). Positive percentage of PD-L1 protein expression was higher in the tissues of L-SCC than that in the tissues of L-ADC (P<0.05). However, there were no correlation between the expression of PD-L1 and age, gender, pathological grades, clinical stages, and lymph node metastasis in L-ADC and L-SCC respectively (all P>0.05). Overall survival rate was evidently lower in the L-ADC patients with positive expression of PD-L1 protein compared to the patients with negative staining of PD-L1 (P<0.01). Multivariate Cox regression analysis further identified that the L-ADC patients of positive expression of PD-L1 protein had a poor prognosis (P<0.01). CONCLUSIONS: The positive percentage of PD-L1 protein expression is higher in the L-SCC patients than that in the L-ADC patients. Positive expression of PD-L1 protein can be served as an independent prognostic factor of poor prognosis in the patients with L-ADC.

Overexpression of p-Akt, p-mTOR and p-eIF4E proteins associates with metastasis and unfavorable prognosis in non-small cell lung cancer.

The Akt (protein kinase B)/mammalian target of rapamycin (mTOR) pathway, which is dysregulated in various cancers, controls the assembly of eukaryotic translation initiation factor 4F (eIF4E) complex. However, whether aberrant expression of phosphorylated Akt (p-Akt), phosphorylated mTOR (p-mTOR) and phosphorylated eIF4E (p-eIF4E) is associated with clinicopathological characteristics in surgically resected non-small cell lung cancer (NSCLC) has been rarely reported. Here, we investigated expression of p-Akt, p-mTOR and p-eIF4E proteins in NSCLC by immunohistochemistry and evaluated their correlation with clinicopathological characteristics and prognostic significance. The results showed that the positive percentage of p-Akt, p-mTOR and p-eIF4E was higher in NSCLC. Additionally, p-mTOR and p-eIF4E was dramatically higher in lung adenocarcinoma (both P<0.05). Most importantly, NSCLC patients with lymph node metastasis had significantly elevated expression of p-Akt, p-mTOR and p-eIF4E (all P<0.05). Positive expression of p-Akt, and any positive expression of p-Akt, p-mTOR and p-eIF4E proteins were positively correlated with clinical stages (both P<0.05). Spearman's rank correlation test revealed that expression of p-Akt was correlated with p-eIF4E and p-mTOR (r = 0.107, P = 0.047; r = 0.287, P<0.001, respectively). Also, p-eIF4E had positive correlation with p-mTOR (r = 0.265, P<0.001). Furthermore, NSCLC patients with increased expression of p-Akt, p-mTOR and p-eIF4E, and any positive expression of above three proteins had lower overall survival rates (all P<0.05). Multivariate Cox regression analysis further indicated thatp-eIF4E was an independent prognostic factor for NSCLC patients (P = 0.046). Taken together, overexpression of p-Akt, p-mTOR and p-eIF4E proteins is associated with metastasis and poor prognosis of NSCLC patients after surgical resection, and positive expression of p-eIF4E protein may act as an independent unfavorable prognostic biomarker for overall survival of NSCLC patients.

Combined Application of Immunohistochemistry and Warthin-Starry Silver Stain on the Pathologic Diagnosis of Cat Scratch Disease.

PURPOSE: Cat scratch disease (CSD) is an infectious disorder caused primarily by the bacterium Bartonella henselae (B. henselae). Immunohistochemistry (IHC) and Warthin-Starry silver stain (WS) are considered to be indispensable to diagnose CSD in combination with morphologic characteristics. In this study, we retrieved and reviewed 46 cases of paraffin-embedded lymphadenitis with histologic and/or clinical suspicion of CSD between 2014 and 2018, and detected B. henselae by IHC and WS, respectively, and evaluated the application significance of IHC and WS for the detection of B. henselae and validated their values in the pathologic diagnosis of CSD. MATERIALS AND METHODS: B. henselae was detected by IHC and WS; validation of 2 methods for detecting B. henselae was evaluated by sensitivity, specificity, false-positive rate, false-negative rate, precision, negative predictive value, and agreement rate. RESULTS: Microscopically, suppurative granulomas and/or multiple stellate microabscesses were observed in the accessory cortex of lymph nodes, especially near the subcapsule. Our results showed that 80.4% (37/46) of cases were positive for B. henselae by IHC, manifesting mainly punctuate, granular, or linear to outline the shape of bacteria. However, the positive rate of B. henselae by the WS method was 52.2% (24/46). There was a significant difference between IHC and WS (P=0.023). Moreover, a positive percentage of B. henselae was 97.8% (45/46), which was detected by the combined application of IHC and WS. The combination of IHC and WS exhibited high sensitivity (97.8%) and good agreement rate (86.5%). CONCLUSION: The combined application of the IHC and WS method may have important clinical advantages, which is with the highest sensitivity and agreement rate for pathologic diagnosis of CSD.

Expression of DR5 and c­FLIP proteins as novel prognostic biomarkers for non­small cell lung cancer patients treated with surgical resection and chemotherapy.

TRAIL­R2 (DR5), one of the death receptors, can activate the extrinsic apoptosis pathway, while cellular FLICE­inhibitory protein (c­FLIP) can inhibit this pathway. Both of them play important roles in the occurrence and development of most tumors. To date, there is no relevant report concerning the relationship between expression of DR5 and c­FLIP protein and clinicopathological/prognostic implications in patients with non­small cell lung cancer (NSCLC) treated with surgical resection and chemotherapy. Thus, the aim of the present study was to investigate the potential prognostic significance of DR5 and c­FLIP in NSCLC patients and their predictive roles in the chemotherapeutic response. In the present study, DR5 and c­FLIP were detected by immunohistochemistry (IHC) in tissue microarrays of NSCLC. The results showed that the expression levels of DR5 and c­FLIP were significantly higher in lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC) tissues compared with levels noted in the non­cancerous control lung tissues (all P<0.05). In addition, DR5 expression was significantly increased in lung ADC (P<0.001), whereas, c­FLIP was higher in lung SCC (P<0.001) and smoker patients with clinical stage III (P=0.019, P=0.016, respectively). In addition, NSCLC patients with overexpression of DR5 and loss of c­FLIP expression exhibited a higher overall survival (OS) rate as determined by Kaplan­Meier analysis (P=0.029, P=0.038, respectively). Multivariate analysis confirmed that high expression of DR5 and loss of c­FLIP expression were independent favorable prognostic factors for NSCLC patients (P=0.016, P=0.035, respectively). In conclusion, overexpression of DR5 and loss of c­FLIP expression may serve as novel favorable prognostic biomarkers for NSCLC patients treated with chemotherapy after radical resection and used as predictors for tumor response to chemotherapy drugs.

Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer.

BACKGROUND: Mcl-1, an anti-apoptotic member of bcl-2 family, together with cleaved poly (ADC-ribose) polymerase (c-PARP) can serve as a marker of cell apoptosis. Previously we reported that treatment of Mnk inhibitor CGP57380 resulted in decreased Mcl-1 expression while increased c-PARP expression in non-small cell lung cancer (NSCLC) cells. In this study, we aimed to investigate association between Mcl-1 expression and clinicopathological features of NSCLC, and their correlation between Mcl-1 and both proliferation index (PI) and apoptotic index (AI) in NSCLC patients. METHODS: Tissue microarrays (TMA) including 350 cases of surgically resected NSCLC were utilize and stained with Mcl-1, Ki-67 and c-PARP antibodies, PI and AI were then evaluated, respectively. RESULTS: Higher Mcl-1 expression and PI were observed in NSCLC compared with non-cancerous lung tissues (non-CLT), while AI was significantly lower in lung adenocarcinoma (ADC) compared with non-CLT. Additionally, Mcl-1 expression in lung ADC was evidently higher than that of in lung squamous cell carcinoma (SCC). The elevated Mcl-1 expression was associated with PI, and inversely related to AI in NSCLC. NSCLC patients with elevated Mcl-1 expression and high PI, or with high Mcl-1 expression and low AI had remarkably shorter overall survival time than these patients with low Mcl-1 expression. CONCLUSIONS: Elevated expression of Mcl-1 might be inversely proportional to disease progression of NSCLC patients by promoting cell proliferation and inhibiting apoptosis, and Mcl-1 might serve as novel biomarker of poor prognosis for NSCLC patients.

Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection.

PURPOSE: G3BP1 is an RNA-binding protein and plays roles in regulating signaling pathway. YB-1 is a DNA/RNA binding protein encoded by YBX1 gene. Phosphorylated AKT (p-AKT) acts as a pivotal molecule in PI3K/AKT pathway. YB-1 drives stress granules (SGs) formation by activating G3BP1 translation under diverse conditions. SGs are involved in many different metabolic and signaling pathways which may include PI3K/AKT/mTOR. So far, there has been no report on the relationship between expression of G3BP1, p-AKT, and YB1 and clinicopathological features/prognosis in surgically resected nonsmall cell lung cancer (NSCLC) patients. METHODS: In this study, data from TCGA (The Cancer Genome Atlas) were downloaded to investigate the mRNA expression of G3BP1 and YB1 (YBX1) and their correlation in NSCLC. Also, expression of G3BP1, YB1, and p-AKT proteins was studied using immunohistochemistry in tissue microarrays of NSCLC and in noncancerous lung tissues. RESULTS: We found that the mRNA expression of G3BP1 and YB1 was higher in NSCLC tissues (both P < .05), and G3BP1 was positively correlated with YB1 in mRNA level (r = .399, P < .001). Also, expression of G3BP1, YB1, and p-AKT proteins was higher in NSCLC tissues (all P < .05). And higher expression of G3BP1 and YB1 proteins was seen in patients with clinical stage II and III compared with stage I (both P < .05). Besides, expression of G3BP1 protein had a positive correlation with YB1 and p-AKT (both P < .05). Moreover, overall survival was shorter in patients with overexpression of G3BP1, YB1, and p-AKT proteins (all P < .05). Multivariate analysis confirmed that overexpression of G3BP1 protein was an independent poorer prognostic factor for NSCLC patients (P = .039). CONCLUSION: G3BP1 may play a crucial role in activating PI3K/AKT/mTOR pathway. G3BP1 might be served as a novel prognostic biomarker for surgically resected NSCLC patients, which afforded new insights into the study on the mechanism and therapy of NSCLC.

Prognostic analysis of patients with mutant and wild-type EGFR gene lung adenocarcinoma.

PURPOSE: The purpose of this study was to investigate the relationship between epidermal growth factor receptor (EGFR) gene mutation and clinicopathological features of lung adenocarcinoma, and the prognostic and therapeutic value of EGFR. METHODS: EGFR gene mutations were detected in 424 patients with lung adenocarcinoma by amplification refractory mutation system (ARMS). RESULTS: The total EGFR gene mutation rate was 55.2% (234/424) and EGFR gene mutation rates were statistically different in gender, smoking status, and pathological degree (P<0.05). The overall survival (OS) time of lung adenocarcinoma patients with mutation of exon 18 was lower than those with mutation of exon 19 and exon 21 (both P<0.05), but no significant difference was seen between those with mutation of exon 19 and exon 21 (P>0.05). Among 424 cases of lung adenocarcinoma, multivariate analysis showed that EGFR gene mutation, age, gender, clinical stages, and pathological degree (P<0.05) were statistically significant prognostic factors. In multivariate analysis, prognostic factors of patients with EGFR gene mutation were associated with EGFR-TKI treatment, surgery treatment, pathological degree, clinical stages, and age (P<0.05), whereas in patients without EGFR gene mutation, prognostic factors were related to surgery treatment, pathological degree, clinical stages, gender, age, and smoking status (P<0.05). CONCLUSION: The OS time of patients with mutation of exon 18 was lower than those of exon 19 and exon 21. EGFR-TKI treatment was an independent positive predictor in patients with EGFR gene mutation. Surgery treatment, age, clinical stages, and pathological degree were independent prognostic factors in Chinese patients with lung adenocarcinoma no matter whether with EGFR gene mutation or not.

Expression of LEF1 and TCF1 (TCF7) proteins associates with clinical progression of nasopharyngeal carcinoma.

AIMS: Our previous study has demonstrated that ß-catenin pathway was abnormally activated in nasopharyngeal carcinoma (NPC). The purposes of the present study are to investigate whether the alterations of LEF1 and TCF1 (TCF7) proteins, the important components of the canonical Wnt/ß-catenin pathway, are associated with clinicopathological features and prognostic implications. METHODS: We collected 391 cases of NPC, 53 non-cancerous control nasopharyngeal mucosa and 28 pairs of NPC and their matched metastases, detected expression of LEF1 and TCF1 (TCF7) proteins in these tissues by immunohistochemistry.  RESULTS: Results showed that there were significantly increased expression of both LEF1 and TCF1 (TCF7) proteins and coexpression of LEF1 and TCF1 (TCF7) in NPC than these in non-cancerous nasopharyngeal mucosa (all p<0.001), as well as LEF1 and coexpression of LEF1 and TCF1 (TCF7) in matched metastasis NPCs than these in the primary NPCs (p=0.003 and p=0.014, respectively). In addition, expression of LEF1 and the coexpression of LEF1 and TCF1 (TCF7) proteins were positively correlated with lymph node metastasis (p=0.001 and p=0.020, respectively), advanced clinical stage (p<0.003 and p=0.027, respectively) and poor survival status of patients with NPC (p<0.001 and p=0.004, respectively). Moreover, multivariate Cox regression analysis identified that the positive expression of LEF1 was the independent poor prognostic factor for overall survival of patients with NPC (p<0.001). CONCLUSIONS: The expression of LEF1 associated positively with TCF1 (TCF7) and clinical progression of NPC, and positive expression of LEF1 protein may act as valuable independent biomarker to predict poor prognosis for patients with NPC.

Elevated HSP90 associates with expression of HIF-1α and p-AKT and is predictive of poor prognosis in nasopharyngeal carcinoma.

AIMS: HSP90, as a molecular chaperone, has numerous substrate proteins, including HIF-1α and p-AKT, but the relationships among HSP90, HIF-1α and p-AKT have not been investigated in NPC. We examined and analysed the correlation between expression of HSP90, HIF-1α and p-AKT and clinicopathological features of NPC. METHODS: We collected 445 cases of NPC and 54 cases of non-cancerous nasopharyngeal epithelia tissues, detected expression of HSP90, HIF-1α and p-AKT proteins in these tissues by immunohistochemistry. RESULTS: The results indicated that overexpression of HSP90, HIF-1α and p-AKT in NPC was significantly higher than that in non-cancerous nasopharyngeal epithelia (P < 0.05). The overexpression of HIF-1α in primary NPC was significantly lower than that in matched lymph node metastatic NPC (P = 0.024) or recurrent NPC (P = 0.039). The overexpression of HSP90 (P < 0.001) and HIF-1α (P = 0.031) was evidently higher in late stage NPC. NPC patients with lymph node metastasis (LNM) had a higher overexpression rate of HSP90 (P < 0.001) than those without LNM. Increased HSP90 expression was positively associated with HIF-1α expression (r = 0.367, P < 0.001) and p-AKT (r = 0.142, P = 0.003) expression in NPC. Furthermore, HIF-1α was also related to p-AKT expression (r = 0.114, P = 0.017). The overall survival rate for NPC patients with up-regulated HSP90 was significantly lower than those with down-regulated HSP90 (P < 0.001), as was found with raised HIF-1α (P = 0.036) and increased p-AKT (P = 0.044). Multivariate Cox regression analysis further identified that HSP90 and HIF-1α were independent poor prognostic factors for NPC. CONCLUSIONS: Taken together, elevated HSP90 was associated with expression of HIF-1α and p-AKT in NPC. Furthermore, high expression of HSP90 and HIF-1α could be used as a novel independent poor prognostic biomarker for patients with NPC.

Roles of exosomes in the carcinogenesis and clinical therapy of non-small cell lung cancer.

Lung cancer, with about 85% being non-small cell lung cancer (NSCLC), is one of the most common malignant tumors and the leading cause of cancer-related death in both men and women. Exosomes are defined as extracellular vesicles with a diameter of 30-100 nm, containing proteins, nucleic acids, lipids, etc., which are secreted by various cells in the microenvironment. Increasing evidences implicate that exosomes act as important molecular vehicles participating in physiological and pathological processes, such as tumor initiation, progression, and response to therapy in a number of human cancers including NSCLC. The aim of this review is to disclose the function of exosomes in NSCLC carcinogenesis, and discuss the potential clinical significance in the diagnosis, prognosis and of treatment NSCLC.

The roles of tumor-derived exosomes in non-small cell lung cancer and their clinical implications.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, and it is one of the leading causes of cancer death in both men and women worldwide due to diagnosis in the advanced stage, rapid metastasis, and recurrence. At present, precision molecular targeted therapeutics directed toward NSCLC driven genes has made great progress and significantly improved the overall survival of patients with NSCLC, but can easily lead to acquired drug resistance. New methods are needed to develop real-time monitoring of drug efficacy and drug resistance, such as new molecular markers for more effective early detection and prediction of prognosis. Exosomes are nano-sized extracellular vesicles, containing proteins, nucleic acids and lipids, which are secreted by various cells, and they play an important role in the development of lung cancer by controlling a wide range of pathways. Tumor-derived exosomes are of great significance for guiding the targeted therapy of NSCLC and exosomes themselves can be a target for treatment. In this review, we describe the potential roles of tumor-derived exosomes and their clinical significance in NSCLC.

MicroRNAs associated with therapy of non-small cell lung cancer.

BACKGROUND & OBJECTIVE: The incidence of non-small cell lung cancer (NSCLC) has been rising over the past several decades. Despite various therapeutic regimens and modern diagnostic techniques are developed, NSCLC still have an extremely poor prognosis due to drug resistance. Therefore, it is critical to find a novel precise diagnosis and effective treatment approach for NSCLC patients. MicroRNAs (MiRNAs) are a class of 18-25nt non-coding small RNAs, which have been shown to be involved profoundly in the pathogenesis such as cellular proliferation, differentiation, development, apoptosis and tumorigenesis in many human tumors including of NSCLC. We reviewed existing research literature regarding correlations between miRNAs and their target's response to anticancer treatment, and summarized the recent findings between miRNAs and therapy availability in NSCLC.

Elevated expression of IRS-1 associates with phosphorylated Akt expression and predicts poor prognosis of breast invasive ductal carcinoma.

Overexpression of insulin receptor substrate 1 (IRS-1) has been reported to promote cell growth, atypical hyperplasia, and carcinogenesis, and phosphorylated Akt (p-Akt) is certified to be involved in many types of cancers such as breast invasive ductal carcinoma (BIDC). However, the relationship between IRS-1 and Akt, as well as the role of expression of IRS-1 in BIDC, has never been reported. The purpose of this research is to investigate the association between expression of IRS-1 and p-Akt proteins and clinicopathological features of BIDC by immunohistochemistry, as well as the survival status. The results showed that the percentage of either elevated expression of IRS-1 or positive p-Akt expression in BIDC was significantly higher than that in control breast tissue from noncancer patients (P < .001 and P = .001, respectively). Overexpression of IRS-1 was evidently associated with positive expression of p-Akt (r = 0.337, P < .001). Also, positive percentage of p-Akt expression was statistically different among different molecular subtypes of BIDC (highest in luminal B BIDC, P = .009). Furthermore, significantly worse overall survival was found in BIDC patients with high expression of IRS-1 and p-Akt than in patients with low expression (P = .006 and P = .004, respectively). The multivariate Cox proportional hazard regression analysis showed that high expression of IRS-1 and positive expression of p-Akt protein were independent poor prognostic factors for patients with BIDC (P = .022 and P = .046, respectively). In conclusion, we report for the first time that overexpression of IRS-1 protein is associated with expression of p-Akt, and overexpression of IRS-1 and positive expression of p-Akt might be independent biomarkers for poor prognosis in BIDC.

Detection and application of circulating tumor cell and circulating tumor DNA in the non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. The ability of cancer cells to break-off from the primary tumor and spread to distant organs is the main cause of death of cancer patients. The detection of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) is a considerable part of liquid biopsy, which contributes to the diagnosis, treatment and prognosis, and especially to identify the targetable mutations of NSCLC. This review is to discuss the detection and application of CTC and ctDNA in the diagnosis, prognostic evaluation and guiding targeted therapy of NSCLC.

Long non-coding RNAs associated with non-small cell lung cancer.

Lung cancer, with 80-85% being non-small cell lung cancer (NSCLC), is the leading cause of cancer-related death in both men and women. Long non-coding RNAs (lncRNAs), always defined as non-protein-coding RNA molecules longer than 200 nucleotides, are now thought as a new frontier in the study of human malignant diseases including NSCLC. As researches continue, increasing number of roles that lncRNAs play in NSCLC has been found, and more and more evidences show lncRNAs have a close relationship with patients' response to radiochemotherapy or molecular therapy. The aim of this review is to disclose the roles that lncRNAs play in NSCLC and how lncRANs influence the treatment of NSCLC.