Edaravone: A Possible Treatment for Acute Lung Injury.

Despite technological advances in science and medicine, acute lung injury (ALI) is still associated with high mortality rates in the ICU. Therefore, finding novel drugs and treatment approaches is crucial to preventing ALI. Drug repurposing is a common practice in clinical research, primarily for drugs that have previously received approval for use in patients, to investigate novel uses of drugs and therapies. One such medication is edaravone, which is a highly effective free-radical scavenger that also has anti-inflammatory, anti-apoptotic, antioxidant, and anti-fibrotic effects. Both basic and clinical studies have shown that edaravone can treat different types of lung injury through its distinct properties. Edaravone exhibits significant protective benefits and holds promising clinical treatment potential for ALI caused by diverse factors, thereby offering a novel approach to treating ALI. This study aims to provide new insights and treatment options for ALI by reviewing both basic and clinical research on the use of edaravone. The focus is on evaluating the effectiveness of edaravone in treating ALI caused by various factors.

Targeting the AMPK/Nrf2 Pathway: A Novel Therapeutic Approach for Acute Lung Injury.

ALI(acute lung injury) is a severe respiratory dysfunction caused by various intrapulmonary and extrapulmonary factors. It is primarily characterized by oxidative stress and affects the integrity of the pulmonary barrier. In severe cases, ALI can progress to ARDS(acute respiratory distress syndrome), a condition that poses a serious threat to the lives of affected patients. To date, the etiological mechanisms underlying ALI remain elusive, and available therapeutic options are quite limited. AMPK(AMP-activated protein kinase), an essential serine/threonine protein kinase, performs a pivotal function in the regulation of cellular energy levels and cellular regulatory mechanisms, including the detection of redox signals and mitigating oxidative stress. Meanwhile, Nrf2(nuclear factor erythroid 2-related factor 2), a critical transcription factor, alleviates inflammation and oxidative responses by interacting with multiple signaling pathways and contributing to the modulation of oxidative enzymes associated with inflammation and programmed cell death. Indeed, AMPK induces the dissociation of Nrf2 from Keap1(kelch-like ECH-associated protein-1) and facilitates its translocation into the nucleus to trigger the transcription of downstream antioxidant genes, ultimately suppressing the expression of inflammatory cells in the lungs. Given their roles, AMPK and Nrf2 hold promise as novel treatment targets for ALI. This study aimed to summarise the current status of research on the AMPK/Nrf2 signaling pathway in ALI, encompassing recently reported natural compounds and drugs that can activate the AMPK/Nrf2 signaling pathway to alleviate lung injury, and provide a theoretical reference for early intervention in lung injury and future research on lung protection.

Free PSA performs better than total PSA in predicting prostate volume in Chinese men with PSA levels of 2.5-9.9 ng ml-1.

This study investigated whether free prostate-specific antigen (fPSA) performs better than total PSA (tPSA) in predicting prostate volume (PV) in Chinese men with different PSA levels. A total of 5463 men with PSA levels of <10 ng ml-1 and without prostate cancer diagnosis were included in this study. Patients were classified into four groups: PSA <2.5 ng ml-1, 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1. Pearson/Spearman's correlation coefficient (r) and receiver operating characteristic (ROC) curves were used to evaluate the ability of tPSA and fPSA to predict PV. The correlation coefficient between tPSA and PV in the PSA <2.5 ng ml-1 cohort (r = 0.422; P < 0.001) was markedly higher than those of the cohorts with PSA levels of 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1 (r = 0.114, 0.167, and 0.264, respectively; all P ≤ 0.001), while fPSA levels did not differ significantly among different PSA groups. Area under ROC curve (AUC) analyses revealed that the performance of fPSA in predicting PV ≥40 ml (AUC: 0.694, 0.714, and 0.727) was better than that of tPSA (AUC = 0.545, 0.561, and 0.611) in men with PSA levels of 2.5-3.9 ng ml-1, 4.0-9.9 ng ml-1, and 2.5-9.9 ng ml-1, respectively, but not at PSA levels of <2.5 ng ml-1 (AUC: 0.713 vs 0.720). These findings suggest that the relationship between tPSA and PV may vary with PSA level and that fPSA is more powerful at predicting PV only in the ''gray zone'' (PSA levels of 2.5-9.9 ng ml-1), but its performance was similar to that of tPSA at PSA levels of <2.5 ng ml-1.

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells.

BACKGROUND: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital-based cohort cases. METHODS: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan-Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. RESULTS: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). CONCLUSIONS: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

DCBLD2 Affects the Development of Colorectal Cancer via EMT and Angiogenesis and Modulates 5-FU Drug Resistance.

Background: DCBLD2 is highly expressed in various cancers, including colorectal cancer. DCBLD2 overexpression promotes tumor occurrence, development, and metastasis. However, DCBLD2 sensitivity to chemotherapy drugs and its mechanism on tumor development are unknown. Methods: DCBLD2 expression differences in cancer and normal tissues were obtained from GEO and TCGA databases. DCBLD2 influence on prognosis was also compared, and the database analysis results were verified via the analysis of clinical samples. GDSC database was used to analyze the effect of DCBLD2 expression difference on 5-FU drug sensitivity on tumor cells. CCK-8, clone formation, scratch, Transwell invasion and migration assays were used to assess DCBLD2 effects on the proliferation, metastasis, and 5-FU drug sensitivity on HCT116 and Caco-2 colorectal cancer cells. Angiogenesis and Matrigel plug assays were used to study the effect of DCBLD2 on angiogenesis. Q-RCR and Western Blot were used to analyze DCBLD2 impact on the EMT signaling pathway, and TAP-MS assay with Co-IP verification was used to identify the downstream target proteins binding to DCBLD2. Results: Both database and clinical sample validation results showed that the expression of DCBLD2 in colorectal cancer tissues was significantly higher than that in normal tissues, leading to poor prognosis of patients. GDSC database analysis showed that DCBLD2 overexpression caused tumor cell resistance to 5-FU. The results of in vitro and in vivo experiments showed that the inhibition of DCBLD2 reduced the proliferation, migration and invasion of colorectal cancer cells, inhibited the angiogenesis of endothelial cells, and enhanced the drug sensitivity to 5-FU. The results of q-RCR and Western Blot experiments showed that the inhibition of DCBLD2 can suppress the EMT signal. The results of TAP-MS assay showed that the proteins bound to DCBLD2 were enriched to the Focal adhesion pathway. The results of Co-IP assay show that DCBLD2 can combine with ITGB1, the key factor of Focal adhesion pathway. Conclusion: DCBLD2 may affect the development of colorectal cancer by regulating cell proliferation and motility, and modulate 5-FU resistance. Down-regulation of DCBLD2 can inhibit EMT signal and angiogenesis. DCBLD2 can combine with ITGB1, the key signal factor of the Focal adhesion pathway.

Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer.

PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.

Hsa_circ_0001946 Inhibits Lung Cancer Progression and Mediates Cisplatin Sensitivity in Non-small Cell Lung Cancer via the Nucleotide Excision Repair Signaling Pathway.

Background: Despite great advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC), early diagnosis remains a challenge because patients usually have advanced lung cancer at the time they are diagnosed. The limited efficacy of conventional chemotherapy is another major problem in the treatment of NSCLC. Based on a published set of sequencing data, we find that hsa_circ_0001946 is a circRNA molecule with a significantly different expression level in three cell lines (human normal lung fibroblasts cell line MRC-5, human NSCLC cell line A549, cisplatin-resistant cell line A549/DDP), NSCLC tissues and paired adjacent normal tissues. We believe that hsa_circ_0001946 may have an effect on the progression of NSCLC and its sensitivity to cisplatin. Methods: We focused on investigating the circular RNA, hsa_circ_0001946. RNA interference of hsa_circ_0001946 was carried out in A549 cell lines to determine the effect of reduced hsa_circ_0001946 expression on lung cancer progression and was analyzed by Cell Counting Kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine, clone formation, Hoechst, wound healing, and transwell assays. The nucleotide excision repair (NER) signaling pathway was identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Moreover, cellular responses to cisplatin were assessed through CCK-8 and flow cytometry assays. Western blot analysis and host-cell reactivation assay were used to determine the effect of hsa_circ_0001946 on NER signaling. Results: In this study, we found that the reduced expression of hsa_circ_0001946 promoted the viability, proliferation, migration, and invasion of NSCLC cells, as well as inhibition of cell apoptosis. Our findings suggest that hsa_circ_0001946 can affect the sensitivity of NSCLC cells to the chemotherapeutic drug cisplatin via modulation of the NER signaling pathway. Conclusions: Our study demonstrated the role of hsa_circ_0001946 in NSCLC pathogenesis, development, and chemosensitivity, and suggests that hsa_circ_0001946 may serve as a novel biomarker for the diagnosis and prediction of platinum-based chemosensitivity in patients with NSCLC.

Circular RNA screening from EIF3a in lung cancer.

Eukaryotic initiation factor 3 (EIF3) is one of the largest and most complex translation initiation factors, which consists of 13 subunits named eukaryotic translation initiation factor 3 subunit A (EIF3a) to EIF3m. EIF3a is the largest subunit of EIF3. Previous studies suggested that EIF3a is a housekeeping gene, recent results have found that EIF3a is closely related to the tumorigenesis and drug resistance. Circular RNAs (circRNAs) derived from biologically important gene can play an important role in gene regulation. However, the mechanism underlying circRNAs' biological functions is not well understood yet. In this work, we screened 31 EIF3a-derived circRNAs, in which two circEIF3as were identified to be correlated with cisplatin drug sensitivity in lung cancer. Two circEIF3as were found involved in RNA-binding proteins-mediated biological processes and may be related to translational regulation according to bioinformatics analyses. CircEIF3as, the transcriptional initiation factor EIF3a transcribed circRNAs, are associated with both drug sensitivity and translation regulation. These findings mean that they may have a functional synergy effect with EIF3a or be valuable therapeutic targets for treatment like EIF3a. This is the first study that exploits circRNAs screening from EIF3a in lung cancer, our findings provide a novel perspective on the function of EIF3a and circEIF3as in lung cancer.

Nucleolar and spindle-associated protein 1 is a tumor grade correlated prognosis marker for glioma patients.

AIMS: Despite therapeutic advances in glioma management including surgery, radiation, and chemotherapy, the improvement of patient outcome is far from satisfactory. Nucleolar and spindle-associated protein 1 (NUSAP1) is an important functional protein during mitosis, and its abnormal expression is implicated in progression of different types of tumors. However, the role of NUSAP1 in gliomas remains unclear. METHODS: NUSAP1 expression in gliomas with different grades was investigated based on GEO glioma datasets. Kaplan-Meier survival analysis was used to evaluate its prognostic significance. In vitro assays were also performed to evaluate effects of NUSAP1 on malignant phenotypes of glioma cells by silencing NUSAP1. RESULTS: NUSAP1 expression was correlated not only with glioma grade but also with prognosis of glioma patients. NUSAP1 depletion suppressed proliferation of U251 cells by inducing cell cycle arrest at G2/M phase and apoptosis. NUSAP1 depletion rendered U251 cells impaired migratory ability as well. CONCLUSION: NUSAP1 is a potential prognosis marker for glioma patients and therapeutic strategies targeting NUSAP1 might hold promise in improving glioma treatment.

LncRNAs and CircRNAs from the same gene: Masterpieces of RNA splicing.

Accumulating evidence has shown that lncRNAs and circRNAs are novel regulators of gene expression. The discovery of numerous lncRNAs and circRNAs, and investigation into their structures and functions will contribute to our understanding of the pathogenesis of diseases as well as better prevention, diagnosis, and treatment of diseases. There is a close relationship between circRNAs and lncRNAs regarding their origins and functions. Recent studies have shown that non-coding linear and circular transcripts can be transcribed from the same gene and are potential super-enhancers modulating gene transcription. In this review, we summarize the categories, characteristics, biological functions and databases of both lncRNAs and circRNAs, focusing on their transcriptions derived from the same gene, which might give us a deeper understanding of and enable us to better recognize and distinguish their physiological roles.

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.

BACKGROUND: The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported. METHODS: Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse-free survival (RFS) and overall survival (OS) was analyzed with Kaplan-Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system. RESULTS: CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8-35.1) vs. 8.7 (6.8-10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2-34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642-0.781] and 0.675[95% CI 0.601-0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699-0.818) vs. 0.660 (95% CI 0.592-0.727); P = 0.029]. CONCLUSIONS: The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma.

Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types. However, the potential biological roles and regulatory mechanisms of lncRNAs in response to cisplatin treatment are poorly understood. Here, we found that lncRNA SFTA1P (surfactant associated 1, pseudogene), highly expressed in lung, was down-regulated in LSCC tissues and could be induced upon cisplatin treatment in LSCC cells. Elevated SFTA1P induced apoptosis and enhanced the sensitivity to cisplatin of LSCC cells. We further identified that hnRNP-U (heterogeneous nuclear ribonucleoprotein U) was down-regulated in LSCCs and positively correlated with patients' poor prognosis as well as SFTA1P. Mechanistic studies revealed that SFTA1P could up-regulate hnRNP-U expression. In addition, we identified that hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A, high expression of which was correlated with good prognosis in LSCC patients. Our findings demonstrated that SFTA1P might serve as a useful biomarker for LSCC diagnosis and a predictor for cisplatin chemotherapy response in patients with LSCC.

Prognostic and predictive values of CDK1 and MAD2L1 in lung adenocarcinoma.

Lung cancer remains as the leading cause of cancer-related death worldwide, and lung adenocarcinoma (LUAD) is the most common histological subtype. This study aims to investigate biomarkers associated with cancer progression and prognosis of LUAD. We integrated expression profiles of 668 lung cancer patients in five datasets from the Gene Expression Omnibus (GEO) and identified a panel of differentially expressed genes (DEGs). Function enrichment analysis highlighted that these genes were closely associated with the carcinogenesis of LUAD, such as cell cycle, ECM-receptor interaction and p53 signaling pathway. Cyclin-dependent kinase 1 (CDK1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1), two critical mitotic checkpoint genes, were selected for further study. Elevated expression of CDK1 and MAD2L1 was validated in an independent LUAD cohort. Kaplan-Meier analysis revealed that CDK1 and MAD2L1 expression was negatively correlated with both overall survival (OS) and relapse-free survival (RFS). In conclusion, CDK1 and MAD2L1 were adverse prognostic biomarkers for LUAD whose increased expression could render patients with LUAD a high risk of cancer recurrence and poor survival, suggesting that they might be applied as potential targets for LUAD treatment.

Targeting DNA Damage Response in the Radio(Chemo)therapy of Non-Small Cell Lung Cancer.

Lung cancer is the leading cause of cancer death worldwide due to its high incidence and mortality. As the most common lung cancer, non-small cell lung cancer (NSCLC) is a terrible threat to human health. Despite improvements in diagnosis and combined treatments including surgical resection, radiotherapy and chemotherapy, the overall survival for NSCLC patients still remains poor. DNA damage is considered to be the primary cause of lung cancer development and is normally recognized and repaired by the intrinsic DNA damage response machinery. The role of DNA repair pathways in radio(chemo)therapy-resistant cancers has become an area of significant interest in the clinical setting. Meanwhile, some studies have proved that genetic and epigenetic factors can alter the DNA damage response and repair, which results in changes of the radiation and chemotherapy curative effect in NSCLC. In this review, we focus on the effect of genetic polymorphisms and epigenetic factors such as miRNA regulation and lncRNA regulation participating in DNA damage repair in response to radio(chemo)therapy in NSCLC. These may provide novel information on the radio(chemo)therapy of NSCLC based on the individual DNA damage response.

A new prognostic histopathologic classification of nasopharyngeal carcinoma.

BACKGROUND: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response. METHODS: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS). RESULTS: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28). CONCLUSIONS: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement.

INTRODUCTION: The rearrangement of the anaplastic lymphoma kinase (ALK) gene accounts for approximately 1%-6% of lung adenocarcinoma cases and defines a molecular subgroup of tumors characterized by clinical sensitivity to ALK inhibitors such as crizotinib. This study aimed to identify the relationship between ALK rearrangement and the clinicopathologic characteristics of non-small cell lung cancer (NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy to ALK rearrangement in NSCLC patients. METHODS: A total of 487 lung cancer patients who underwent testing for ALK rearrangement in our department were included in this study. ALK rearrangement was examined by using fluorescence in situ hybridization (FISH) assay. RESULTS: Among the 487 patients, 44 (9.0%) were diagnosed with ALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non-smokers and of a young age (≤ 58 years old), the frequency of ALK rearrangement was 20.3% (25/123). Short overall survival (OS) was associated with non-adenocarcinoma tumor type (P = 0.006), poorly differentiated tumors (P = 0.001), advanced-stage tumors (P < 0.001), smoking history (P = 0.008), and wild-type epidermal growth factor receptor (EGFR) (P = 0.008). Moreover, patients with poorly differentiated and advanced-stage tumors had a shorter time to cancer progression compared with those with well differentiated (P = 0.023) and early-stage tumors (P = 0.001), respectively. CONCLUSIONS: ALK-rearranged NSCLC tends to occur in younger individuals who are either non-smokers or light smokers with adenocarcinoma. Patients with ALK rearrangement might benefit from ALK inhibitor therapy.

Effect of Raf kinase inhibitor protein expression on malignant biological behavior and progression of colorectal cancer.

The Raf kinase inhibitor protein (RKIP) is a novel metastasis suppressor. RKIP was previously found to have low expression in a colorectal cancer (CRC) patient cohort by immunohistochemistry. However, the role of RKIP in CRC remains undetermined. In the present study, immunohistochemistry was performed to compare RKIP expression between 129 paired stage II CRC and adjacent non-tumorous tissues. The correlations between clinical parameters, prognosis and RKIP expression were evaluated. To investigate the effect of RKIP on proliferation and metastasis, RKIP was overexpressed and knocked down in colon cancer cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell and wound-healing assays were performed. Murine models were established to confirm the influence of RKIP on malignant tumor phenotypes in vivo. Our results showed that RKIP expression was significantly decreased in the CRC tissues compared to the adjacent non­cancerous tissues (p<0.001) and was correlated with the risk of relapse in stage II CRC (p<0.05). Overexpression of RKIP suppressed HCT116 cell metastasis in vitro and in vivo, whereas knockdown of RKIP expression in SW480 cells and its murine model increased metastatic ability (p<0.05). No effect of RKIP on cell proliferation in CRC was observed. These data suggest that RKIP is an important metastasis-suppressor gene in CRC. The re-expression of RKIP could be a potential therapeutic target for antimetastatic strategies for CRC.

The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients.

To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.

MicroRNA-30a promotes invasiveness and metastasis in vitro and in vivo through epithelial-mesenchymal transition and results in poor survival of nasopharyngeal carcinoma patients.

Although microRNA-30a (miR-30a) has been shown to regulate cancer metastasis, the molecular mechanism has not yet been clearly elucidated in nasopharyngeal carcinoma (NPC). The present study was to investigate the miR-30a expression pattern and its potential functions and further to identify its target gene and corresponding clinical applications in NPC. MiR-30a was identified to be down-regulated in NPC primary tumors compared with metastatic tumors using quantitative real-time PCR. Furthermore, over-expression of miR-30a transfected with precursor increased the ability of metastasis and invasion of NPC tumor cells in vivo and in vitro. E-cadherin was screened as a putative target gene of miR-30a by computational algorithms. Luciferase reporter assays showed that over-expression of miR-30a directly reduced the activity of a luciferase transcript combined with the 3'-untranslated region (3'-UTR) of E-cadherin. Kaplan-Meier survival analysis and log-rank test were analyzed for 1077 NPC patients for overall survival, indicating that a high expression of E-cadherin was beneficial for NPC prognosis (P = 0.001). Importantly, NPC patients with high expression of E-cadherin had much lower risk of poor prognosis (hazard ratio = 0.757, P = 0.017) using multivariate analysis. In conclusion, miR-30a could play an important role in regulating NPC metastasis and potentially provide useful guidelines for individualized therapy.

High expression of zinc-binding protein-89 predicts decreased survival in esophageal squamous cell cancer.

BACKGROUND: Zinc-binding protein-89 (ZBP-89), a Krüppel-type four-zinc finger transcription factor, is associated with many cellular functions, including cell growth, differentiation, and apoptosis. It has been reported to be involved in several human cancers. However, ZBP-89 expression pattern and its clinical significance have not yet been investigated in esophageal squamous cell cancer. METHODS: In this study, immunostaining was performed to detect ZBP-89 expression in esophageal squamous cell cancer, and then the correlations between ZBP-89 expression and both clinicopathologic variables and overall survival were analyzed. RESULTS: Compared with adjacent normal tissues, ZBP-89 expression was significantly upregulated in esophageal squamous cell cancer tissues. Increased ZBP-89 expression was associated with N category (p = 0.009) and TNM stage (p = 0.023). Patients with high expression of ZBP-89 demonstrated shortened overall survival compared with those with low expression of ZBP-89 (mean overall survival, 56.961 months versus 76.029 months; p < 0.001). Multivariate Cox regression analysis indicated that ZBP-89 expression had a significant, independent predictive value for survival of esophageal squamous cell cancer (relative risk, 1.581; p = 0.024). CONCLUSIONS: Our data show that increased expression of ZBP-89 is associated with poor prognosis for esophageal squamous cell cancer patients and may act as a novel, useful, and independent prognostic indicator for esophageal squamous cell cancer. Further studies are warranted.