Androgen receptor suppresses lung cancer invasion and increases cisplatin response via decreasing TPD52 expression.

Lung cancer, as the most commonly diagnosed malignancy, still accounts for the leading cause of cancer-related deaths worldwide. The high rate of mortality and tumor recurrence has prompted clinicians and scientists to urgently explore new targets for improved treatment. Previous studies have indicated a potential role of the androgen receptor (AR) in the progression of non-small cell lung cancer (NSCLC). However, the precise mechanisms underlying this association, particularly its relation to TPD52-mediated cell invasion and cisplatin (DDP) response, have not been fully elucidated. Therefore, further investigation is necessary to gain a better understanding of these mechanisms and their potential implications for lung cancer treatment. In this study, we discovered that AR can suppress NSCLC cell invasion and increase cisplatin response by downregulating the expression of circular RNA (circRNA), specifically circ-SLCO1B7. This suppression is achieved through the direct binding of AR to the 5' promoter region of the host gene SLCO1B7. The decreased expression of circ-SLCO1B7, mediated by AR, released miR-139-5p back to the RISC (RNA induced silencing complex), where it bonds to the 3' untranslated region (3'UTR) of Tumor Protein D52 (TPD52) messenger RNA, resulting in TPD52 reduction. The in vivo data also validated the functional contribution of AR/circ-SLCO1B7/miR-139-5p/TPD52 axis to lung cancer progression. Furthermore, analysis of human NSCLC databases and clinical specimens confirmed the association of the AR/circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway with NSCLC progression. Collectively, the results from our study suggest that AR can suppress lung cancer cell invasion and increase DDP response by modulating the circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway. Targeting this novel signaling pathway may be a new therapeutic strategy to effectively constrain NSCLC development.

Cuproptosis Depicts Immunophenotype and Predicts Immunotherapy Response in Lung Adenocarcinoma.

BACKGROUND: Although significant progress has been made in immunotherapy for lung adenocarcinoma (LUAD), there is an urgent need to identify effective indicators to screen patients who are suitable for immunotherapy. Systematically investigating the cuproptosis-related genes (CRGs) in LUAD may provide new ideas for patients' immunotherapy stratification. METHOD: We comprehensively analyzed the landscape of 12 CRGs in a merged TCGA and GEO LUAD cohort. We investigated the associations between tumor microenvironment and immunophenotypes. We utilized a risk score to predict the prognosis and immunotherapy response for an individual patient. Additionally, we conducted CCK-8 experiments to evaluate the impact of DLGAP5 knockdown on A549 cell proliferation. RESULT: We utilized an integrative approach to analyze 12 CRGs and differentially expressed genes (DEGs) in LUAD samples, resulting in the identification of two distinct CRG clusters and two gene clusters. Based on these clusters, we generated immunophenotypes and observed that the inflamed phenotype had the most abundant immune infiltrations, while the desert phenotype showed the poorest immune infiltrations. We then developed a risk score model for individual patient prognosis and immunotherapy response prediction. Patients in the low-risk group had higher immune scores and ESTIMATE scores, indicating an active immune state with richer immune cell infiltrations and higher expression of immune checkpoint genes. Moreover, the low-risk group exhibited better immunotherapy response according to IPS, TIDE scores, and Imvigor210 cohort validation results. In addition, our in vitro wet experiments demonstrated that DLGAP5 knockdown could suppress the cell proliferation of A549. CONCLUSION: Novel cuproptosis molecular patterns reflected the distinct immunophenotypes in LUAD patients. The risk model might pave the way to stratify patients suitable for immunotherapy and predict immunotherapy response.

PSMA1, a Poor Prognostic Factor, Promotes Tumor Growth in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC) has a poor clinical prognosis and lacks effective targeted therapy. This study is aimed at investigating the role of PSMA1 (proteasome subunit alpha type-1) in LUSC. The differential expression genes (DEGs) in LUSC were retrieved from The Cancer Genome Atlas (TCGA) by "edgR" algorithm and by "limma" R package. Then, the relationship between genes and overall survival (OS) was explored by the least absolute shrinkage and selection operator (LASSO) and multivariate Cox (multi-Cox) regression. Next, the PSMA1 expression in tissues of LUSC was detected by IHC, qRT-PCR, and western blot (WB). Moreover, the effects of PSMA1 on the proliferation and viability of LUSC cell were explored by cell counting kit 8 (CCK-8) assays, colony formation assays, and flow cytometry (FCM) analysis. All 4421 DEGs were screened by TCGA database, and 26 genes associated with OS were selected by multi-Cox. Based on TCGA database, PSMA1 was highly expressed in tissues of LUSC patients, and OS and FP of patients with PSMA1 overexpression were significantly lower than those of patients with low PSMA1 expression. Furthermore, PSMA1 knockdown significantly decreased the proliferation of LUSC cells and promoted the apoptosis of LUSC cells, and these effects were reversed by PSMA1 overexpression. The results of this project supported that PSMA1 might be a critical gene regulating the development of LUSC and has the potential to be explored as a prognostic biomarker of LUSC.

Bioinformatics construction and experimental validation of a cuproptosis-related lncRNA prognostic model in lung adenocarcinoma for immunotherapy response prediction.

Cuproptosis is a newly form of cell death. Cuproptosis related lncRNA in lung adenocarcinoma (LUAD) has also not been fully elucidated. In the present study, we aimed to construct a prognostic signature based on cuproptosis-related lncRNA in LUAD and investigate its association with immunotherapy response. The RNA-sequencing data, clinical information and simple nucleotide variation of LUAD patients were obtained from TCGA database. The LASSO Cox regression was used to construct a prognostic signature. The CIBERSORT, ESTIMATE and ssGSEA algorithms were applied to assess the association between risk score and TME. TIDE score was applied to reflect the efficiency of immunotherapy response. The influence of overexpression of lncRNA TMPO-AS1 on A549 cell was also assessed by in vitro experiments. The lncRNA prognostic signature included AL606834.1, AL138778.1, AP000302.1, AC007384.1, AL161431.1, TMPO-AS1 and KIAA1671-AS1. Low-risk group exhibited much higher immune score, stromal score and ESTIMATE score, but lower tumor purity compared with high-risk groups. Also, low-risk group was associated with a much higher score of immune cells and immune related function sets, indicating an immune activation state. Low-risk patients had relative higher TIDE score and lower TMB. External validation using IMvigor210 immunotherapy cohort demonstrated that low-risk group had a better prognosis and might more easily benefit from immunotherapy. Overexpression of lncRNA TMPO-AS1 promoted the proliferation, migration and invasion of A549 cell line. The novel cuproptosis-related lncRNA signature could predict the prognosis of LUAD patients, and helped clinicians stratify patients appropriate for immunotherapy and determine individual therapeutic strategies.

Prognostic significance of tumor-associated macrophages polarization markers in lung cancer: a pooled analysis of 5105 patients.

BACKGROUND: The prognostic significance of tumor-associated macrophages (TAMs) in patients with lung cancer (LCa) remains controversial. We therefore conducted the present study to systematically evaluate the role of different TAMs markers and histologic locations on the prognosis of LCa. METHODS: Searches of Web of Science, PubMed, and EMBASE databases were performed up to 28 February 2022. The pooled analysis was conducted in random-effect or fixed-effects model with hazard risk (HR) and 95% confidence interval (CI) for survival data including overall survival (OS), and disease-free survival (DFS) from raw or adjusted measures, according to different TAMs markers and histologic locations. RESULTS: Including a total of 5105 patients from 30 eligible studies, the results indicated that the total count of CD68+ TAMs was negatively associated with OS and DFS, which was also observed in the relationship of CD68+ or CD204+ TAMs in tumor stroma (TS) with OS and DFS (all P<0.05). Conversely, higher CD68+ TAMs density in tumor nest (TN) or TN/TS ratio of CD68+ TAMs predicted better OS (all P<0.05). Similarly, higher HLA-DR+ TAMs density was correlated with better OS in TN and TS (all P<0.05). Besides, neither nest CD163+ TAM density nor stromal CD163+ TAM density was a prognostic factor in LCa patients (all P>0.05). CONCLUSION: Our study indicated that different TAMs markers and histologic locations could bring about different prognostic effects in LCa patients. Great understanding of the infiltration modes of TAMs may contribute to improve outcomes of LCa patients.

Integrative bioinformatic analysis identified IFIT3 as a novel regulatory factor in psoriasis.

Psoriasis is an autoimmune skin disease with poor prognosis. Currently, there is no cure for psoriasis and the pathogenic mechanism of psoriasis remains unclear. Our study aims to explore key regulators underlying psoriasis and potential targets for psoriasis treatment. RNA-seq data of psoriasis and normal tissues were extracted from Gene Expression Omnibus database to screen differentially expressed genes (DEGs). Weighted correlation network analysis (WGCNA) was conducted to identify key gene modules correlated with psoriasis. Enrichment analysis was used to characterize identified genes. The expression of identified genes was verified in a data set with various types of psoriasis lesion tissues and six psoriasis and healthy control tissues by quantitative polymerase chain reaction and immunohistochemistry assays. And the biological functions of IFIT3 in keratinocytes were determined by colony formation assays, Cell Counting Kit-8, and enzyme-linked immunosorbent assays. A total of 594 overlapped genes (370 upregulated and 224 downregulated) were selected as DEGs between psoriasis and normal tissues in three independent data sets. These genes were enriched in interferon-related pathway and cytokine-related pathway. Weighted correlation network analysis identified several gene modules that were associated with psoriasis. Overlapped genes between gene modules and DEGs were associated with interferon-related pathway and T cell activities. Among these genes, OAS1, USP18, and IFIT3 had higher expression levels in psoriasis vulgaris (PV) and nonpustular palmoplantar psoriasis (NPPP) tissues but not Palmoplantar Pustular Psoriasis (PPPP). Meanwhile, these results were confirmed in our independent psoriasis tissue cohort. And results of in vitro experiments showed that inhibition of IFIT3 significantly impaired the proliferation capacity and CXCL1, CCL20, IL-1ß, and IL-6 secretion of keratinocytes. Our study identified key genes and pathways underlying the pathogenesis of psoriasis through the conduct of integrated analysis. OAS1, USP18, and IFIT3 could be potential targets for the treatment of psoriasis. IFIT3 can promote the proliferation and immune activation of keratinocytes and facilitates the development of psoriasis.

Estrogen receptor beta promotes lung cancer invasion via increasing CXCR4 expression.

Lung cancer is one of the most lethal malignant tumors in the world. The high recurrence and mortality rate make it urgent for scientists and clinicians to find new targets for better treatment of lung cancer. Early studies indicated that estrogen receptor ß (ERß) might impact the progression of non-small-cell lung cancer (NSCLC). However, the detailed mechanisms, especially its linkage to the CXCR4-mediated cell invasion, remain unclear. Here we found that ERß could promote NSCLC cell invasion via increasing the circular RNA (circRNA), circ-TMX4, expression via directly binding to the 5' promoter region of its host gene TMX4. ERß-promoted circ-TMX4 could then sponge and inhibit the micro RNA (miRNA, miR), miR-622, expression, which can then result in increasing the CXCR4 messenger RNA translation via a reduced miRNA binding to its 3' untranslated region (3'UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of NSCLC cells confirmed the in vitro data, and the human NSCLC database analysis and tissue staining also confirmed the linkage of ERß/miR-622/CXCR4 signaling to the NSCLC progression. Together, our findings suggest that ERß can promote NSCLC cell invasion via altering the ERß/circ-TMX4/miR-622/CXCR4 signaling, and targeting this newly circ-TMX4/miR-622/CXCR4 signaling may help us find new treatment strategies to better suppress NSCLC progression.

MAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade.

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. Besides repressing growth, inhibiting MAPK6 sensitized cancer cells to mTOR kinase inhibitors. MAPK6 overexpression is associated with decreased overall survival and the survival of patients with lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer. MAPK6 expression also correlated with AKT phosphorylation at S473 in human cancer tissues. We conclude that MAPK6 can promote cancer by activating AKT independent of mTORC2 and targeting MAPK6, either alone or in combination with mTOR blockade, may be effective in cancers.

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.

MICAL2 is a novel nucleocytoplasmic shuttling protein promoting cancer invasion and growth of lung adenocarcinoma.

MICAL2 is a tumor-promoting factor involved in cell migration, invasion, deformation, and proliferation not yet fully explored in lung adenocarcinoma (LUAD). This study demonstrated that MICAL2 was overexpressed and cytoplasm-enriched in LUAD tissues. Moreover, high cytoplasmic MICAL2 and/or total MICAL2 expression levels were positively correlated with lymphatic metastasis and shorter overall survival in LUAD patients. MICAL2 promoted LUAD cell proliferation, migration, invasion, and epithelial to mesenchymal transition-all of which involved the AKT and myosin-9 pathways. Furthermore, MICAL2 was identified as a nucleoplasm shuttling protein dependent on myosin-9 and its C-terminal fragment. MICAL2-ΔC-enriched in the nucleus-had less impact on tumor malignancy in LUAD cells in vitro and in vivo. Tumor promotion by MICAL2 was reduced by nuclear-export inhibitor, myosin-9 inhibitor, or si-myosin-9-all of which effectively inhibited MICAL2's nuclear export. Finally, the expression and subcellular location as well as clinical significance of MICAL2 and myosin-9 were analyzed across TCGA data and LUAD tissue arrays. Our data revealed that MICAL2 overexpression and nuclear export were associated with cancer progression; inhibiting its expression and/or nuclear export may provide a new target for LUAD therapy.

Association between cancer concealment and the survival of the patients with non-small cell lung carcinoma.

OBJECTIVE: To explore the relationship between cancer awareness and the survival of the patients with non-small cell lung carcinoma (NSCLC).
 Methods: A total of 865 NSCLC patients were screened for the risk factors, including age, gender, address, tumor/lymph nodes/metastasis (TNM) stage, and cancer awareness. Survival of the patients was calculated by Kaplan-Meier method and Cox regression analysis.
 Results: After an average observation time of 304 d (ranging from 0 to 4 718 d), 62 of the 394 patients in the cancer awareness group survived, whereas 26 of the 471 patients in the cancer concealment group survived. Cancer-specific and all-cause survival was poorer in the cancer concealment group (P<0.001 for each, log-rank test). Cox multivariate regression analysis showed that cancer concealment displayed significantly lower cancer-specific survival [hazard ratio (HR)=1.534, 95% confidence interval (CI) 1.320 to 1.784, P<0.001] and all-cause survival (HR=1.558, 95% CI 1.346 to 1.803, P<0.001).
 Conclusion: Cancer concealment is associated with a poor survival of NSCLC patients, which may prohibit the patients from obtaining the real "right to survival".

MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling.

MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.

SH2B1 promotes NSCLC cell proliferation through PI3K/Akt/mTOR signaling cascade.

BACKGROUND: Non-small cell lung cancer (NSCLC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers. The objective of this study was to investigate the role SH2B1 and the underlying molecular mechanism in NSCLC. METHODS: Cell functional analysis and cell line-derived xenograft model were performed to determine SH2B1 potential roles on NSCLC cell proliferation in vitro and in vivo. In vitro assays were performed to identify signal molecular mechanisms. Subsequently, 104 patients with NSCLC undergoing primary surgical resection were recruited to evaluated expression of SH2B1 and Akt/mTOR signaling markers by immunohistochemical staining to determine their clinicopathologic significance. RESULTS: Modulation of SH2B1 expression levels had distinct effects on cell proliferation, cell cycle and apoptosis in the NSCLC cell lines A549 and H1299. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the Akt/mTOR markers, p-Akt and p-mTOR, and downregulation of PTEN to promote NSCLC cell proliferation, while silencing SH2B1 had the opposite effect. In human NSCLC specimens, SH2B1 expression levels were positively associated with Akt/mTOR signaling pathway markers. CONCLUSIONS: The SH2B1/Akt/mTOR/PTEN axis is required for regulating NSCLC cell proliferation and might prove to be a promising strategy for restraining tumor progression in NSCLC patients.

SH2B1 promotes epithelial-mesenchymal transition through the IRS1/ß-catenin signaling axis in lung adenocarcinoma.

Lung adenocarcinoma (LADC), the most prevalent type of human lung cancer, is characterized by many molecular abnormalities. SH2B1, a member of the SH2-domain containing family, have recently been shown to act as tumor activators in multiple cancers, including LADC. However, the mechanisms underlying SH2B1 overexpression are not completely understood. Here, we reported that SH2B1 expression levels were significantly upregulated and positively associated with EMT markers and poor patient survival in LADC specimens. Modulation of SH2B1 levels had distinct effects on cell proliferation, cell cycle, migration, invasion, and morphology in A549 and H1299 cells in vitro and in vivo. At the molecular level, overexpression of SH2B1 resulted in the upregulation of the EMT markers, especially induced ß-catenin accumulation and activated ß-catenin signaling to promote LADC cell proliferation and metastasis, while silencing SH2B1 had the opposite effect. Furthermore, ectopic expression of SH2B1 in H1299 cells increased IRS1 expression level. Reduced expression of IRS1 considerably inhibited H1299 cell proliferation, migration, and invasion which were driven by SH2B1 overexpression. Collectively, these results provide unequivocal evidence to establish that SH2B1-IRS1-ß-catenin axis is required for promoting EMT, and might prove to be a promising strategy for restraining tumor progression in LADC patients.

PRKAR1A is a functional tumor suppressor inhibiting ERK/Snail/E-cadherin pathway in lung adenocarcinoma.

Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma. The low levels of PRKAR1A transcript were correlated with tumor progression and poor overall survival. The re-expression of PRKAR1A in H1299 cells suppressed the tumor cell proliferation and migration; stable knockdown (KD) of PRKAR1A in A549 cells enhanced this function both in vitro and in vivo. Moreover, KD of PRKAR1A in A549 cells promoted the statistical colonization of circulating tumor cells to the lungs in nude mice. These effects by PRKAR1A were attributed to inhibiting E-cadherin expression. Elevated E-cadherin significantly suppressed the PRKAR1A-KD induced cell proliferation and migration. Most notably, deletion of PRKAR1A inhibited E-cadherin by activating ERK/Snail signaling. In conclusion, PRKAR1A was a potent suppressor, and through the inhibition of PRKAR1A-ERK-Snail-E-cadherin axis could serve as a potential therapeutic target.

[PRKAR1α expression in non-small cell lung cancer and its clinicopathologic significance].

OBJECTIVE: To evaluate the expression of cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1α) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological features.
 Methods: PRKAR1α expressions in 79 NSCLC patients and matched adjacent non-carcinoma tissues were analyzed by using qRT-PCR and immunohistochemistry.
 Results: The negative rates of PRKAR1α protein in NSCLC, lung squamous cell carcinoma (SCL) and lung adenocarcinoma (ACL) were 58.2%, 77.8%, 32.4%, respectively. Compared to the matched adjacent non-carcinoma tissues, there were significant differences in levels of PRKAR1α mRNA and protein in ACL (P<0.05), but not in SCL and overall NSCLC (P>0.05). The expression of PRKAR1α protein was positively correlated with histological type, TNM stage, and lymph node metastasis (P<0.05). Tumor size and histogenesis differentiation were not related to the decreased PRKAR1α (P>0.05).
 Conclusion: Low expression of PRKAR1α in ACL might be involved in the pathogenesis, which might serve as a novel diagnostic candidate.

MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC.

BACKGROUND: Lung cancer is the most common malignancies worldwide. However, the detailed molecular mechanisms underlying lung cancer progression are still not completely clear. MicroRNAs are small noncoding RNAs which occupy a crucial role of cancer metastasis. Accumulating evidence suggests that miR-361 plays important roles in human carcinogenesis. However, its precise biological role remains largely elusive, especially in lung cancer. This study examined the role of miR-361-3p in non-small cell lung cancer (NSCLC). METHODS: Real-time quantitative PCR (qRT-PCR) was used to analyze the expression of miR-361-3p in NSCLC tissue and in compared adjacent non-cancerous tissues. The effect of miR-361-3p on proliferation was evaluated by CCK8 and colony formation assays. The effect of miR-361-3p on migration and invasion was evaluated by transwell assays. Western blotting and immunohistochemical staining were applied to analyze the expression of target proteins and downstream molecule, and the luciferase reporter assay to assess the target genes of miR-361-3p in non-small cell lung cancer cells. RESULTS: miR-361-3p was significantly decreased in NSCLC tissue and cell lines, and its expression levels were highly correlated with lymph node metastasis (P < 0.01) and TNM stages (P < 0.05). Down-regulation of miR-361-3p promoted cell growth, proliferation, colony formation, invasion and migration in vitro, and promoted proliferation and metastasis in vivo (P < 0.01); whereas up-regulation of miR-361-3p had the contrary effects. The luciferase reporter assay showed that SH2B1 was a direct target gene of miR-361-3p. Enforced expression of miR-361-3p inhibited the expression of SH2B1 significantly and the restoration of SH2B1 expression reversed the inhibitory effects of miR-361-3p on NSCLC cell proliferation and metastasis. CONCLUSIONS: miR-361-3p functions as a novel tumor suppressor in NSCLC and the anti-oncogenic activity may involve its inhibition of the target gene SH2B1. These findings suggest the possibility for miR-361-3p as a therapeutic target in NSCLC.

[Effect of perioperative treatment with ambroxol on lung cancer patients after video-assisted thoracic surgery lobectomy].

OBJECTIVE: To evaluate the influence of perioperative intravenous administration of ambroxol on pulmonary function, postoperative complications, postoperative hospital stay, and cost after video-assisted thoracic surgery lobectomy for lung cancer. METHODS: Sixty patients who underwent video-assisted thoracic surgery lobectomy for lung cancer in Xiangya Hospital, Central South University between May 2011 and May 2012 were randomly assigned into 2 groups: An ambroxol group (n=30) and a control group (n=30). In the ambroxol group, patients were given ambroxol (1 000 mg/d) on the day of operation and on the first 3 postoperative days. In control group, placebo was given. The pulmonary function tests, arterial blood gases, incidence of perioperative morbidity, postoperative mechanical ventilation time, duration of ICU stay, length and costs of postoperative hospital stay were compared between the 2 groups. RESULTS: The 2 groups were well matched for demographics and operative variables. The ambroxol group showed better the percent predicted forced expiratory volume in 1 second (FEV1%), the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC%), the percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) and arterial oxygen pressure than the control group. The postoperative pulmonary complications was significantly reduced, the duration of mechanical ventilation and the length of ICU stay were shortened, and the length and costs of postoperative hospital stay were significantly decreased in the ambroxol group compared with the control group (all P<0.05). CONCLUSION: Perioperative intravenous administration of ambroxol can improve the postoperative lung function, reduce the incidence of pulmonary complications, shorten the length of postoperative hospital stay, and lower the total cost of hospitalization after video-assisted thoracic surgery lobectomy for lung cancer.