Mutational profile evaluates metastatic capacity of Chinese colorectal cancer patients, revealed by whole-exome sequencing.

Colorectal cancer (CRC) is the third most common cancer and the prevalence rate of CRC is increasing in the China. In this study, whole-exome sequencing (WES) was performed on primary tissues of 47 CRC Chinese patients including 22 metastatic and 25 non-metastatic patients. By comparison with data from western colorectal cancer patients in the Cancer Genome Atlas (TCGA), we identified a number of genes that are more likely to be mutated in Chinese colorectal cancer patients, such as MUC12, MUC12, MUC2, MUC4, HYDIN and KMT2C. Interestingly, MUC family genes including MUC12, MUC2 and MUC4, have mutation rates of >20%, while the mutation frequency was extremely low in western colorectal cancer patients, which were <3% in TCGA and 0% in Memorial Sloan Kettering Cancer Center (MSKCC). We detected metastasis-specific mutated genes including TCF7L2, MST1L, HRNR and SMAD4, while MUC4, NEB, FLG and RFPL4A alteration is more prevalent in the non-metastasis group. Further analysis reveals mutation genes in metastasis group are more focus in the Wnt and Hippo signaling pathway. APC, SMAD4 and TCF7L2 accounted for the major genetic abnormalities in this pathway. In conclusion, this study identified the unique characteristics of gene mutations in Chinese patients with colorectal cancer, and is a valuable reference for personalized treatment in Chinese CRC patients.

Construction of web-based prediction nomogram models for cancer-specific survival in patients at stage IV of hepatocellular carcinoma depending on SEER database. / 基于SEER数据库构建IVæœŸè‚ç»†èƒžç™Œæ‚£è€ ç™Œç—‡ç‰¹å¼‚æ€§ç”Ÿå­˜æœŸçš„ç½‘ç»œé¢„æµ‹åˆ—çº¿å›¾æ¨¡åž‹ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Hepatocellular carcinoma (HCC) prognosis involves multiple clinical factors. Although nomogram models targeting various clinical factors have been reported in early and locally advanced HCC, there are currently few studies on complete and effective prognostic nomogram models for stage IV HCC patients. This study aims to creat nomograms for cancer-specific survival (CSS) in patients at stage IV of HCC and developing a web predictive nomogram model to predict patient prognosis and guide individualized treatment. METHODS: Clinicopathological information on stage IV of HCC between January, 2010 and December, 2015 was collected from the Surveillance, Epidemiology, and End Results (SEER) database. The patients at stage IV of HCC were categorized into IVA (without distant metastases) and IVB (with distant metastases) subgroups based on the presence of distant metastasis, and then the patients from both IVA and IVB subgroups were randomly divided into the training and validation cohorts in a 7꞉3 ratio. Univariate and multivariate Cox regression analyses were used to analyze the independent risk factors that significantly affected CSS in the training cohort, and constructed nomogram models separately for stage IVA and stage IVB patients based on relevant independent risk factors. Two nomogram's accuracy and discrimination were evaluated by receiver operator characteristic (ROC) curves and calibration curves. Furthermore, web-based nomogram models were developed specifically for stage IVA and stage IVB HCC patients by R software. A decision analysis curve (DCA) was used to evaluate the clinical utility of the web-based nomogram models. RESULTS: A total of 3 060 patients were included in this study, of which 883 were in stage IVA, and 2 177 were in stage IVB. Based on multivariate analysis results, tumor size, alpha-fetoprotein (AFP), T stage, histological grade, surgery, radiotherapy, and chemotherapy were independent prognostic factors for patients with stage IVA of HCC; and tumor size, AFP, T stage, N stage, histological grade, lung metastasis, surgery, radiotherapy, and chemotherapy were independent prognostic factors for patients with stage IVB HCC. In stage IVA patients, the 3-, 6-, 9-, 12-, 15-, and 18-month areas under the ROC curves for the training cohort were 0.823, 0.800, 0.772, 0.784, 0.784, and 0.786, respectively; and the 3-, 6-, 9-, 12-, 15-, and 18-month areas under the ROC curves for the validation cohort were 0.793, 0.764, 0.739, 0.773, 0.798, and 0.799, respectively. In stage IVB patients, the 3-, 6-, 9-, and 12-month areas under the ROC curves for the training cohort were 0.756, 0.750, 0.755, and 0.743, respectively; and the 3-, 6-, 9-, and 12-month areas under the ROC curves for the validation cohort were 0.744, 0.747, 0.775, and 0.779, respectively; showing that the nomograms had an excellent predictive ability. The calibration curves showed a good consistency between the predictions and actual observations. CONCLUSIONS: Predictive nomogram models for CSS in stage IVA and IVB HCC patients are developed and validated based on the SEER database, which might be used for clinicians to predict the prognosis, implement individualized treatment, and follow up those patients.

SPP2 plays a role in the tumorigenesis of hepatocellular carcinoma: A bioinformatic based analysis. / 基于生物信息学分析SPP2在肝癌发生过程中的作用（英文）.

OBJECTIVES: Hepatocellular carcinoma (HCC) patients at the same stage exhibit different prognosis, and the underlying molecular mechanism remains unclear. This study aims to identify the key genes impacting the prognosis of HCC patients. METHODS: Differentially expressed gene analyses were performed between HCC samples and normal ones, and between patients with long overall survival (OS) and those with short OS, in TCGA-LIHC and GSE14520 datasets. The Kaplan-Meier method with log-rank test was used to evaluate the role of secreted phosphoprotein 2 (SPP2) in the prognosis of HCC patients. Gene set enrichment analysis (GSEA) was used to understand the difference of enriched signaling pathways between SPP2-stratified HCC subgroups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential functional pathways in which SPP2 might participate. RESULTS: SPP2 was significantly down-regulated in tumors when compared with normal tissues, or in tumor samples with short OS when compared with those with long OS [fold change (FC)>2 and false discovery rate (FDR)<0.05]. Low expression of SPP2 was associated with worse clinicopathological features like vascular invasion (P=1.6e-05), poor cancer status (with tumor, P=0.021), advanced T stage (T3 or T4, P=4.5e-04), advanced TNM stage (stage III or IV, P=3.1e-04), and with unfavorable prognosis (shorter OS, P=0.002). Gene enrichment analyses revealed that SPP2 might involve in the metabolic homeostasis of HCC and in the development of liver fibrosis and cirrhosis. CONCLUSIONS: SPP2 might inhibit the development of liver fibrosis and cirrhosis and the tumorigenesis of HCC, and analogs of SPP2 might be potential drugs in the prevention of these diseases.

Serum levels of tumor markers and their clinical significance in epithelial ovarian cancer. / ä¸Šçš®æ€§åµå·¢ç™Œè¡€æ¸ ä¸­è‚¿ç˜¤æ ‡å¿—ç‰©æ°´å¹³åŠå ¶ä¸´åºŠæ„ä¹‰ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Tumor markers have been widely used clinically. Detection of serum CA125 is one of the commonly used clinical methods for early screening and early diagnosis of epithelial ovarian cancer, but it is difficult to diagnose epithelial ovarian cancer with a single specific tumor marker. In this study, the combinatorial tumor marker detection method was used to compare the value of each tumor marker alone and different combinations in the diagnosis of epithelial ovarian cancer. METHODS: The clinical data of patients with epithelial ovarian cancer (n=65) and ovarian benign disease (n=29) were collected. Multiple tumor marker protein chip was used to detect cancer antigen 125 (CA125), carbohydrate antigen 242 (CA242), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (ß-HCG), carcinoembryonic antigen (CEA), cancer antigen 199 (CA199), neuron-specific enolase (NSE), Ferritin, cancer antigen 153 (CA153), and human growth hormone (HGH) serum levels, and to compare the differences between the benign and malignant ovarian tumors. The correlation between tumor markers and clinicopathologic features for ovarian epithelial carcinoma was analyzed by χ2 test. Spearman rank analysis showed the correlation between CA125 expression level and other tumor markers in epithelial ovarian cancer and the correlation between age and the above 10 tumor markers. Sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and diagnostic efficiency were used to evaluate the diagnostic value of single tumor marker and the combination of tumor markers. RESULTS: The levels of ß-HCG, NSE, CA153, and CA125 in the epithelial ovarian cancer group were higher than those in the ovarian benign disease group. The level of NSE in the serum of patients with epithelial ovarian cancer was related to the clinical stage of patients. In addition, the levels of CA242, ß-HCG, CEA, NSE, Ferritin, CA153 in the serum of patients with epithelial ovarian cancer were positively correlated with CA125 (rs=0.497, P<0.001; rs=0.612, P<0.001; rs=0.358, P=0.003; rs=0.680, P<0.001; rs=0.322, P=0.009; rs=0.609, P<0.001, respectively), and the levels of ß-HCG, Ferritin, CA153 were positively correlated with the patient's age (rs=0.256, P=0.040; rs=0.325, P=0.008; rs=0.249, P=0.046, respectively). In the diagnosis of epithelial ovarian cancer, the sensitivity, Youden index, and diagnostic efficiency of CA125 detection alone were higher than the results of the other 9 separate detections. When CA153, CA199, CA242, Ferritin, and CEA were combined with CA125, the sensitivity of the combined detection of different combinations was higher than that of CA125 alone. The combined detection sensitivities of CA125+CEA and CA125+Ferritin+CEA were 89.2% and 90.8%, respectively, and the diagnostic efficiencies were both 84.1%, which were higher than those of other combinations. The Youden index of CA125+CEA joint detection was 0.616, which was higher than those of other combinations. CONCLUSIONS: CA125 has a high diagnostic value in the diagnosis of epithelial ovarian cancer. The detection of combined tumor markers in serum has higher sensitivity and specificity in epithelial ovarian cancer.

H19/miR-107/HMGB1 axis sensitizes laryngeal squamous cell carcinoma to cisplatin by suppressing autophagy in vitro and in vivo.

Laryngeal squamous cell carcinoma (LSCC) is the most common malignant tumor, which occurs in the head and neck. Current treatments for LSCC are all largely weakened by increasing drug resistance. Our study aimed to investigate the effects of long noncoding RNA (lncRNA) H19 on drug resistance in LSCC. In our study, we found that the level of H19 was sharply upregulated in LSCC tissues and drug-resistant cells compared with the control. Besides, the expression of high-mobility group B1 (HMGB1) was elevated, and microRNA107 (miR-107) was suppressed in drug-resistant cells compared with the control. Further study revealed that the interference of H19 by short hairpin RNA (shRNA) effectively suppressed high autophagy level and obvious drug resistance in drug-resistant cells. Besides that, miR-107 was predicted as a target of H19 and inhibiting effects of H19 shRNA on autophagy and drug resistance were both reversed by miR-107 inhibitor. Moreover, HMGB1 was predicted as a target of miR-107 in LSCC cells and knockdown of HMGB1 was able to suppress autophagy and drug resistance in LSCC cells. In addition, our investigation demonstrated that H19 shRNA exerted an inhibiting effect on autophagy and drug resistance by downregulating HMGB1 by targeting miR-107. Finally, the in vivo experiment revealed that LV-H19 shRNA strongly suppressed drug resistance compared with the usage of cisplatin individually. Taken together, our research indicated an H19-miR-107-HMGB1 axis in regulating the autophagy-induced drug resistance in LSCC in vitro and in vivo, providing novel targets for molecular-targeted therapy and broadening the research for LSCC.

MiR-130b promotes the progression of oesophageal squamous cell carcinoma by targeting SASH1.

MiR-130b and SAM and SH3 domain containing 1 (SASH1) play an important role in many types of human cancers. The aim of our research was to study their interactions in the process of the proliferation and aggressiveness of oesophageal squamous cell carcinoma (ESCC) cells. Microarray analysis was done to screen the differentially expressed genes in the ESCC tissues. miR-130b and SASH1 mRNA levels in the ESCC tissues and cells were detected by qRT-PCR. Dual luciferase reporter system was used to verify the target relationship between miR-130b and SASH1. The effects of miR-130b on SASH1 expression were explored by western blot in KYSE30 and TE1 cell lines. CCK-8 assay, flow cytometry, Transwell, and wound healing assays were conducted to explore the effects of miR-130b and SASH1 in vitro. In addition, in vivo experiments were conducted to study the roles of miR-130b and SASH1. miR-130b was highly expressed, while SASH1 was the opposite in both the ESCC tissues and cells. The expression of SASH1 was inhibited by the direct binding of miR-130b. The inhibition of miR-130b reduced the proliferation and aggressiveness of ESCC cells, while it also induced apoptosis and cell cycle arrest in the ESCC cells by suppressing SASH1. The in vivo assay suggested that the overexpression of miR-130b promoted the growth of ESCC tumours. MiR-130b was up-regulated in the ESCC tumour tissues and cells, acting as a tumour promoter. A stimulating effect was demonstrated on ESCC cell growth and aggressiveness by suppressing SASH1, which is an anti-oncogene.

Upregulated expression of PTTG1 is associated with progression of pancreatic cancer.

Background: Pancreatic cancer (PC) is an aggressive disease with a very poor prognosis. The insidious onset, rapid progression, and resistance to conventional therapies mark the imperious need for novel biomarkers and therapeutic targets. The pituitary tumor transforming gene 1 (PTTG1), implicated in tumorigenesis and cellular transformation, has been studied in various cancers, however, its role and mechanisms in PC remain to be elucidated for better understanding the disease pathology and in enhancing patient management strategies. Methods: The present study examined the PTTG1 messenger RNA (mRNA) expression levels and clinical significance through meta-analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) was used to measure PTTG1 protein levels in PC and adjacent non-cancerous tissues. A correlation was observed between PTTG1 expression and some clinical characteristics based on the TCGA and IHC data. Univariate and multivariate Cox regressions were used to identify independent prognostic factors. Kaplan-Meier (KM) survival analysis was performed. The co-expressed genes of PTTG1 were determined by integrating online tools, and the enrichment analyses were performed to determine PTTG1-related pathways and hub co-expressed genes. Results: PTTG1 was highly expressed in PC tissues based on the TCGA, GEO, and IHC data. The combined standard mean difference (SMD) values of PTTG1 expression based on TCGA and GEO databases was 1.02 [95% confidence interval (CI): 0.74-1.30]. The area under the curve (AUC) based on the summary receiver operating characteristic (sROC) curve was 0.93 (95% CI: 0.90-0.95). PTTG1 overexpression was remarkably correlated with an inferior overall survival (OS). A total of 367 genes were identified as co-expressed genes of PTTG1 in PC and were mainly involved in the cell cycle pathway. The four identified core genes were CDK1, CCNA2, CDC20, and MAD2L1. Conclusions: The upregulated expression of PTTG1 plays an essential role in PC's progression as a biomarker.

ADNP is associated with immune infiltration and radiosensitivity in hepatocellular carcinoma for predicting the prognosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal diseases due to its high faculty of invasiveness and metastasis. Activity-dependent neuroprotective protein (ADNP) has been regarded as an oncogene in bladder cancer and ovarian cancer. However, the role of ADNP in the regulation of tumor immune response, development, and treatment resistance in HCC remains unknown and is worth exploring. METHODS: The correlation between ADNP and prognosis, immune cell infiltration, immune checkpoints, chemokines, tumor mutation burden, microsatellite instability, and genomic mutation of pan-cancer cohorts in The Cancer Genome Atlas was analyzed. ADNP expression in HCC cell lines, HCC and the adjacent normal tissues was measured by western blotting and immunochemistry. Nomogram was constructed to predict the survival of patients with HCC based on the ADNP expression and significant clinical characteristics. The potential biological functions and impacts on radiotherapy of ADNP in HCC cell lines were verified by vitro experiments. RESULTS: ADNP was upregulated in most cancers and patients with elevated ADNP expression were related to poor survival in several types of cancers including HCC. Functional enrichment analysis showed ADNP participated in the pathways correlated with coagulation cascades and DNA double strand break repair. Further, ADNP exhibited a negative correlation with the immune score, stromal score, estimated score, and chemokines, and a positive correlation with cancer-associated fibroblasts, myeloid-derived suppressor cells, neutrophils, regulatory T cells, and endothelial cells. Immunochemistry and western blotting results demonstrated ADNP was up-regulated in HCC. Vitro experiments verified that suppressing the ADNP expression significantly inhibited the proliferation, invasion and migration and elevated the radiosensitivity via decreasing DNA damage repair in HCC. CONCLUSION: ADNP might play an oncogene and immunosuppression role in tumor immune infiltration and response, thus influencing the prognosis. Its downregulation could attenuate the proliferation, invasion, migration, radioresistance of HCC. Our results indicated the potential of ADNP as a promising biomarker to predict the survival of HCC patients, providing a theoretical basis for novel integrative strategies.

A web-based nomogram model for predicting the overall survival of hepatocellular carcinoma patients with external beam radiation therapy: A population study based on SEER database and a Chinese cohort.

Background: External beam radiation therapy (EBRT) for hepatocellular carcinoma (HCC) is rarely used in clinical practice. This study aims to develop and validate a prognostic nomogram model to predict overall survival (OS) in HCC patients treated with EBRT. Method: We extracted eligible data of HCC patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. Those patients were randomly divided into a training cohort (n=1004) and an internal validation cohort (n=429), and an external validation cohort composed of a Chinese cohort (n=95). A nomogram was established based on the independent prognostic variables identified from univariate and multivariate Cox regression analyses. The effective performance of the nomogram was evaluated using the concordance index (C-index), receiver operating characteristic curve (ROC), and calibration curves. The clinical practicability was evaluated using decision curve analysis (DCA). Results: T stage, N stage, M stage, AFP, tumor size, surgery, and chemotherapy were independent prognostic risk factors that were all included in the nomogram to predict OS in HCC patients with EBRT. In the training cohort, internal validation cohort, and external validation cohort, the C-index of the prediction model was 0.728 (95% confidence interval (CI): 0.716-0.740), 0.725 (95% CI:0.701-0.750), and 0.696 (95% CI:0.629-0.763), respectively. The 6-, 12-,18- and 24- month areas under the curves (AUC) of ROC in the training cohort were 0.835 、0.823 、0.810, and 0.801, respectively; and 0.821 、0.809 、0.813 and 0.804 in the internal validation cohort, respectively; and 0.749 、0.754 、0.791 and 0.798 in the external validation cohort, respectively. The calibration curves indicated that the predicted value of the prediction model performed well. The DCA curves showed better clinical practicability. In addition, based on the nomogram, we established a web-based nomogram to predict the OS of these patients visually. Conclusion: Based on the SEER database and an independent external cohort from China, we established and validated a nomogram to predict OS in HCC patients treated with EBRT. In addition, for the first time, a web-based nomogram model can help clinicians judge the prognoses of these patients and make better clinical decisions.

CD38: A Significant Regulator of Macrophage Function.

Cluster of differentiation 38 (CD38) is a cell surface glycoprotein and multifunctional extracellular enzyme. As a NADase, CD38 produces adenosine through the adenosine energy pathway to cause immunosuppression. As a cell surface receptor, CD38 is necessary for immune cell activation and proliferation. The aggregation and polarization of macrophages are affected by the knockout of CD38. Intracellular NAD+ levels are reduced by nuclear receptor liver X receptor-alpha (LXR) agonists in a CD38-dependent manner, thereby reducing the infection of macrophages. Previous studies suggested that CD38 plays an important role in the regulation of macrophage function. Therefore, as a new marker of macrophages, the effect of CD38 on macrophage proliferation, polarization and function; its possible mechanism; the relationship between the expression level of CD38 on macrophage surfaces and disease diagnosis, treatment, etc; and the role of targeting CD38 in macrophage-related diseases are reviewed in this paper to provide a theoretical basis for a comprehensive understanding of the relationship between CD38 and macrophages.

Retrospective study of hypofractionated stereotactic radiotherapy combined with whole brain radiotherapy for patients with brain metastases.

BACKGROUND AND PURPOSE: To evaluate the clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) combined with whole brain radiotherapy (WBRT) in patients with brain metastases (BMs). MATERIALS AND METHODS: From May 2018 to July 2020, 50 patients (111 lesions) received HFSRT (18 Gy/3F) + WBRT (40 Gy/20F). The RECIST 1.1 and RANO-BM criteria were used to evaluate treatment efficacy. Five prognostic indexes (RPA, GPA, SIR, BS-BM, and GGS) were applied. The primary endpoint was intracranial local control (iLC). Secondary endpoints were overall survival (OS) and the safety of treatment. RESULTS: Intracranial objective response rates (iORR) using the RECIST 1.1 and RANO-BM criteria were 62.1% and 58.6%, respectively. The iLC rate was 93.1%, the 6- and 12-month iLC rates were 90.8% and 57.4%, respectively. The median intracranial progression-free survival (iPFS) was not reached (range 0-23 months). The 6-, 12-, and 24-month OS rates were 74.2%, 58.2%, and 22.9%, respectively. The KPS score showed statistical significance in univariate analysis of survival. The 6, 12, and 24 month OS rates for patients with KPS ≥ 70 were 83.8%, 70.5%, and 29.7%, respectively. The median survival time (MST) for all patients and for patients with KPS ≥ 70 were 13.6 and 16.5 months, respectively. Sex, KPS score, and gross tumor volume were significant factors in the multivariate analysis of survival. OS was significantly associated with RPA, SIR, BS-BM, and GGS classes. No acute toxicities of grade 3 or higher were noted. CONCLUSION: HFSRT combined with WBRT is a safe and effective local treatment modality for BM patients.

FRA-1: A key factor regulating signal transduction of tumor cells and a potential target molecule for tumor therapy.

Fos-related antigen-1 (FRA-1) is a member of activator protein-1 (AP-1) transcription factor superfamily, and FRA-1 is highly expressed in colon cancer, breast cancer, gastric cancer, lung cancer, bladder cancer, and other tumors. The expression level of FRA-1 is closely related to the processes of tumor cell proliferation, apoptosis, transformation, migration, and invasion, which is a potential therapeutic target and prognostic factor for many tumors. Clarifying the detailed mechanism of action of FRA-1 could provide the theoretical basis for tumor diagnosis, treatment, and prognosis, and is of great significance for the study of tumor etiology and pathogenesis. In this paper, the expression levels and influencing factors of FRA-1 in various tumor tissues and cells are summarized, as well as the effect of FRA-1 expression level on the biological behavior of tumor cells and the signal transduction mechanism. At the same time, the signal transduction mechanism of FRA-1 in inflammation was expounded. In addition, the related metabolites, drugs and non-coding RNA that affect the expression and function of FRA-1 were summarized. Finally, it illustrates that FRA-1 may be taken as a key factor for tumor prognosis and a potential therapeutic target. This review provides a theoretical basis for the systematic understanding of the relationship between FRA-1 and tumors, its function, and possible mechanism.

Prognostic Factors of Colorectal Cancer: A Comparative Study on Patients With or Without Liver Metastasis.

BACKGROUND: Radical or palliative surgery with subsequent adjuvant therapy is the routine treatment for stage II/III colorectal cancer(CRC) and some stage IV CRC patients. This study aimed to clarify the prognostic clinicopathological and genetic factors for these patients. METHODS: Fifty-five stage II-IV CRC patients undergoing surgery and adjuvant therapy were recruited, including patients without liver metastasis(5 at stage II, 21 at stage III) and with liver metastasis(29 at stage IV). Genetic alterations of the primary cancer tissues were investigated by whole exome sequencing(WES). Patients were followed up to 1652 days(median at 788 days). RESULTS: The mutational landscape of primary CRC tissue of patients with or without liver metastasis was largely similar, although the mutational frequency of TRIM77 and TCF7L2 was significantly higher in patients with liver metastasis. Several main driver gene co-mutations, such as TP53-APC, APC-KRAS, APC-FRG1, and exclusive mutations, such as TP53-CREBBP, were found in patients with liver metastasis, but not in patients without liver metastasis. No significant difference was found between the two groups in aberrant pathways. If stage II-IV patients were studied altogether, relapse status, SUPT20HL1 mutations, Amp27_21q22.3 and Del8_10q23.2 were independent risk factors(P<0.05). If patients were divided into two groups by metastatic status, surgery types and Amp6_20q13.33 were independent risk factors for patients without liver metastasis(P<0.05), while TRIM77 mutations were the only independent risk factor for patients with liver metastasis(P<0.05). CONCLUSIONS: Surgery types and Amp6_20q13.33 were independent risk factors for CRC patients without liver metastasis, and TRIM77 mutations were the independent risk factor for CRC patients with liver metastasis.

Increased expression of microRNA-335 predicts a favorable prognosis in primary gallbladder carcinoma.

BACKGROUND: MicroRNAs (miRNAs) display aberrant expression patterns and functional abnormalities in many types of cancer. However, their roles in primary gallbladder carcinoma (PGC) have not been well documented. miR-335 has been demonstrated to be involved in tumorigenesis of several cancers in the digestive system. The aim of this study was to investigate the clinical significance of miR-335 in PGC. METHODS: miR-335 expression in 166 human PGC tissues and matched adjacent nondysplastic gallbladder epithelia was measured by real-time quantitative polymerase chain reaction (RT-PCR) assay. RESULTS: The expression level of miR-335 was significantly lower in PGC tissues than that in nondysplastic gallbladder epithelia (P<0.001). Of 166 PGC patients, 96 (57.83%) had reduced expression of miR-335. Additionally, the expression of miR-335 was significantly lower in PGC tissues with high histologic grade (P=0.02), advanced pathologic T stage (P=0.009) and clinical stage (P=0.008), and with positive lymph node metastasis (P=0.001). In univariate analysis by log-rank test, histologic grade (P=0.03), pathologic T stage (P=0.008), clinical stage (P=0.01), lymph node metastasis (P<0.001), and miR-335 expression (P<0.001) were significant prognostic factors for overall survival of PGC patients. Multivariate analysis further revealed that pathologic T stage (P=0.02), lymph node metastasis (P=0.008), and miR-335 expression (P=0.006) maintained independent prognostic influence on overall survival. CONCLUSION: This study offers convincing evidence for the first time that miR-335 was downregulated in a majority of PGC patients and may be associated with the aggressive tumor behaviors. Loss of miR-335 expression may be a useful marker for clinical outcome and a therapeutic target for PGC.

MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma.

The matrix metalloprotease-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC), we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9%) and 58 (68.2%) tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM) stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS) than those with negative ESCC (P = 0.002 and 0.003, respectively). Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR) = 2.836, 95% confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95%CI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95%CI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95%CI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95%CI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95%CI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95%CI = 1.256-2.881) as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.

MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma

The matrix metalloprotease-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC), we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9 percent) and 58 (68.2 percent) tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM) stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS) than those with negative ESCC (P = 0.002 and 0.003, respectively). Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR) = 2.836, 95 percent confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95 percentCI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95 percentCI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95 percentCI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95 percentCI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95 percentCI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95 percentCI = 1.256-2.881) as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.