LncRNA-EWSAT1 promotes hepatocellular carcinoma metastasis via activation of the Src-YAP signaling axis.

Regardless of the improvements in diagnostic and therapeutic methods, the clinical outcomes of hepatocellular carcinoma (HCC) patients remain poor. Although accumulating evidence indicates that lncRNAs (long noncoding RNAs) are essential within the control of tumorigenesis and the metastasis of cancer, the underlying mechanisms remain largely unknown. This work explored the pattern of expression and functional significance of a newly found lncRNA, Ewing sarcoma-associated transcript 1 (EWSAT1), in HCC metastasis. The results indicated that EWSAT1 was upregulated significantly in HCC relative to that in normal tissues and was correlated with an aggressive phenotype and low patient survival. Functional experiments demonstrated that EWSAT1 could promote proliferation and HCC cell metastasis both in vitro and in vivo. Mechanistically, EWSAT1 binds directly to Yes-associated protein (YAP), promotes Sarcoma gene (Src)-induced phosphorylation of YAP, facilitates nuclear translocation of YAP, and consequently, activates the transcription of Hippo-YAP signaling target genes involved in cancer evolution. This study found that EWSAT1 plays a crucial role in HCC metastasis and that it has the potential to be a prognosis biomarker and a target for therapeutics.

[Correlation of NK cell RIPK1 with Prognosis of Acute Myeloid Leukemia Patients with FLT3-ITD Mutation].

OBJECTIVE: To investigate the correlation of NK cell receptor-interacting serine/threonine kinase 1（RIPK1） activity and expression with prognosis of acute myeloid leukemia (AML) patients with FLT3-ITD mutation. METHODS: A total of 132 AML patients with FLT3-ITD mutation and 136 AML patients with FLT3-WT were selected. Clinical data and the number, length and rearrangement ratio of FLT3-ITD mutations were collected. The ratio of CD4+ T cells, regulatory T cells（Tregs）, CD8+ T cells, B cells, natural killer cells（NK cells） and macrophage in peripheral blood（PB） were analyzed by flow cytometry. Correlation of NK cell ratio with FLT3-ITD mutation number, length and rearrangement ratio was analyzed by Pearson correlation analysis. Western blot and RT-qPCR were used to detect RIPK1 protein and mRNA levels in NK cells, respectively. Plasma RIPK activity was detected by ELISA, and Pearson corre-lation analysis was performed for the correlation of RIPK with FLT3-ITD mutation number, length and rearrangement ratio. Kaplan-Meier curve was used to analyze the survival rate of AML patients with FLT3-ITD mutation. RESULTS: Compared with AML patients with FLT3-WT, the white blood cell count in patients with FLT3-ITD mutation significantly increased, PB and BM blasts significantly decreased. There was no significant change in PB CD3+ T cells, Tregs, CD8+ T cells, B cells, M1 and M2 type macrophage of AML patients with FLT3-WT and FLT3-ITD mutation；Compared with AML patients with FLT3-WT, CD4+ T cells significantly decreased, NK cells significantly increased in AML patients wtih FLT3-ITD mutation. NK cells ratio in AML patients with FLT3-ITD mutation significantly positively correlated with the number of FLT3-ITD mutations and rearrangement bases. Plasma RIPK1 activity, RIPK1 protein and mRNA levels in NK cells of AML patients with FLT3-ITD were significantly lower than those of AML patients with FLT3-WT, and negatively correlated with the number of FLT3-ITD mutations, the length of rearranged bases (≥52 bp) and the ratio of rearranged bases. The survival rate of AML patients with FLT3-ITD mutation in low RIPK1 activity after Rydapt treatment was significantly higher than that in high RIPK1 activity. CONCLUSION: The prognosis of AML patients with FLT3-ITD mutation closely relates with plasma RIPK1 activity and RIPK1 expression in NK cells.

ONECUT2 Accelerates Tumor Proliferation Through Activating ROCK1 Expression in Gastric Cancer.

BACKGROUND: Transcription factors (TFs) are key regulators which control gene expression during cancer initiation and progression. In the current study, we aimed to explore the proliferative function and clinical significance of TFs in gastric cancer (GC). METHODS: Differential analysis was used to investigate the overall expression difference between normal and tumor tissues of each TF in TCGA-STAD cohort. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the mRNA expression of one cut homeobox 2 (ONECUT2) in GC tissues. Western blot analysis was conducted to confirm the protein knockdown efficiency. Cell counting, colony formation, and GC xenograft model assays were performed to confirm the proliferative function of ONECUT2 in GC cells. Gene set enrichment analysis (GESA) and qRT-PCR were conducted to confirm the affected signaling pathways and downstream targets of ONECUT2. RESULTS: Our data indicated that a TF named ONECUT2 was highly expressed in GC and correlated with patients' poor prognosis. Importantly, knockdown of ONECUT2 dramatically decreased GC cells proliferation, whereas overexpression of ONECUT2 promoted carcinogenesis in GC. Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed that the upregulating ONECUT2 induced the activation of Wnt signaling pathway and cell cycle regulation pathway. We further identified that ONECUT2 boosted gastric cancer cell proliferation through enhancing ROCK1 (Rho associated coiled-coil containing protein kinase 1) mRNA expression. High level of ROCK1 expression rescued proliferative behavior of ONECUT2-deficient GC cells. CONCLUSION: Our findings demonstrated that ONECUT2 promoted GC cells proliferation through activating ROCK1 expression at the DNA level, suggesting that ONECUT2-ROCK1 axis might be a potential therapeutic target in GC.

PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer.

Background: Transcriptional factors (TFs) are responsible for orchestrating gene transcription during cancer progression. However, their roles in gastric cancer (GC) remain unclear. Methods: We analyzed the differential expressions of TFs and, using GC cells and tissues, investigated plexin C1 (PLXNC1) RNA levels, as well as PLXNC1's clinical relevance and functional mechanisms. The molecular function of PLXNC1 was evaluated in vitro and in vivo. Kaplan-Meier curves and the log-rank test were used to analyze overall survival (OS) and disease-free survival (DFS). Results: PLXNC1 was frequently up-regulated in GC and associated with poor prognosis. The expression level of PLXNC1 could serve as an independent biomarker to predict a patient's overall survival. Notably, knockdown of PLXNC1 significantly abolished GC cell proliferation, and migration, and overexpression of PLXNC1 accelerated carcinogenesis in GC. The gene set enrichment analysis (GSEA) indicated that high-expression of PLXNC1 was positively correlated with the activation of epithelial-mesenchymal transition (EMT), TNF-α, and IL-6/STAT3 signaling pathways. PLXNC1 promoted proliferation and migration of GC cells through transcriptional activation of the interleukin 6 signal transducer (IL6ST), which could rescue the malignant behavior of PLXNC1-deficient GC cells. Conclusions: Our study demonstrated that the PLXNC1 plays an oncogenic role in GC patients. The PLXNC1-IL6ST axis represents a novel potential therapeutic target for GC.

Analysis of lymph node metastasis in early gastric cancer: a single institutional experience from China.

BACKGROUND: Lymph node metastasis (LNM) has a strong influence on the prognosis of patients with early gastric cancer (EGC). The aim of this study was to reveal the incidence of LNM and evaluate risk factors for LNM to determine the appropriate treatment for EGC in a Chinese population. METHODS: Patients who underwent radical gastrectomy with lymph node dissection for EGC between 2012 and 2017 were retrospectively analyzed. Univariate and multivariate analyses were conducted to identify clinicopathological features that were risk factors for LNM. RESULTS: A total of 1033 patients with EGC were enrolled. Of these patients, 668 (64.7%) were men, and 365 (35.3%) were women, ranging in age from 19 to 82 years (mean 56.9 ± 10.9 years). LNM was detected in 173(16.7%) patients with EGC. Among 508 patients with mucosal cancer, 44 (8.7%) patients had LNM. In 525 patients with submucosal cancer, the incidence of LNM was 24.6% (129/525). The age, gender, tumor size, type of differentiation, Lauren classification, and lymphovascular and perineural invasion showed a significant correlation with the rate of LNM in EGC by univariate and multivariate analyses. Patients with submucosal gastric cancer had an older age, a higher proportion of proximal lesion, larger tumor size, more frequent lymphovascular invasion, perineural invasion, and more LNM than patients with mucosal gastric cancer. CONCLUSIONS: Our study revealed a relatively high incidence of LNM in EGC, compared with Japanese and Korean cohorts. Female sex, large tumor size, undifferentiated-type, and lymphovascular invasion were independent risk factors for LNM in EGC. Radical gastrectomy with lymphadenectomy should be performed in EGC patients with a high risk of LNM.

Impact of Age on the Prognosis of Operable Gastric Cancer Patients: An Analysis Based on SEER Database.

To investigate the impact of age on the clinicopathological features and survival of patients with gastric cancer (GC), and hope to better define age-specific patterns of GC and possible associated risk factors.Using the surveillance, epidemiology, and end results (SEER) database to search the patients who diagnosed GC between 2007 and 2011 with a known age. The overall and 5-year gastric cancer specific survival (CSS) data were obtained using Kaplan-Meier plots. Multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.A total of 7762 GC patients treated with surgery during the 4-year study period were included in the final study cohort. We divided into five subgroups according to the different age ranges. The overall 5-year cause-specific survival (CSS) was 60.3% in Group 1 (below 45 years), 60.3% in the Group 2 (45-55 years), 61.2% in Group 3 (56-65 years), 59.2% in Group 4 (66-75 years), and 59.2% in Group 5 (older than 76 years). Kaplan-Meier plots showed that patients older than 76 years had the worst 5-year CSS of 56.0% rate in all the subgroups. Age, tumor size, primary site, histological type, and Tumor Node Metastasis stage were identified as significant risk factors for poor survival on univariate analysis (all P < 0.001, log-rank test). Additionally, as the age increased, the risk of death for GC demonstrated a significant increase.In conclusion, our analysis of the SEER database revealed that the prognosis of GC varies with age. Patients at age 56 to 65 group have more favorable clinicopathologic characteristics and better CSS than other groups.

[Research Advances on Extranodal Nasal Type NK/T Cell Lymphoma--Review].

Extranodal NK/T cell lymphoma is a relatively uncommon type of non-Hodgkin's lymphoma, which is prevalently distributed in Asia and South America, and is highly associated with Epstein-Barr virus (EBV) infection. Due to its highly aggressive course and poor response to treatment because of its multi-drug resistance, for the timebeing there is not yet a definite treatment strategy. The clinical manifestation, pathological diagnosis and the progress of treatment methods of ENTNKCL are reviewed below.

Impact of lymphatic and/or blood vessel invasion in stage II gastric cancer.

AIM: To determine the prognostic value of lymphatic and/or blood vessel invasion (LBVI) in patients with stage II gastric cancer. METHODS: From January 2001 to December 2006, 487 patients with histologically confirmed primary gastric adenocarcinoma were diagnosed with stage II gastric cancer according to the new 7th edition American Joint Committee on Cancer stage classification at the Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Shanghai Cancer Center. All patients underwent curative gastrectomy with standard lymph node (LN) dissection. Fifty-one patients who died in the postoperative period, due to various complications or other conditions, were excluded. Clinicopathological findings and clinical outcomes were analyzed. Patients were subdivided into four groups according to the status of LBVI and LN metastases. These four patient groups were characterized with regard to age, sex, tumor site, pT category, tumor grading and surgical procedure (subtotal resection vs total resection), and compared for 5-year overall survival by univariate and multivariate analysis. RESULTS: The study was composed of 320 men and 116 women aged 58.9 ± 11.5 years (range: 23-88 years). The 5-year overall survival rates were 50.7% and the median survival time was 62 mo. Stage IIa cancer was observed in 334 patients, including 268 T3N0, 63 T2N1, and three T1N2, and stage IIb was observed in 102 patients, including 49 patients T3N1, 51 T2N2, one T1N3, and one T4aN0. The incidence of LBVI was 28.0% in stage II gastric cancer with 19.0% (51/269) and 42.5% (71/167) in LN-negative and LN-positive patients, respectively. In 218 patients (50.0%), there was neither a histopathologically detectable LBVI nor LN metastases (LBVI(-)/LN(-), group I); in 51 patients (11.7%), LBVI with no evidence of LN metastases was detected (LBVI(+)/LN(-), group II). In 167 patients (38.3%), LN metastases were found. Among those patients, LBVI was not determined in 96 patients (22.0%) (LBVI(-)/LN(+), group III), and was determined in 71 patients (16.3%) (LBVI(+)/LN(+), group IV). Correlation analysis showed that N category and the number of positive LNs were significantly associated with the presence of LBVI (P < 0.001). The overall 5-year survival was significantly longer in LN-negative patients compared with LN-positive patients (56.1% vs 42.3%, P = 0.015). There was a significant difference in the overall 5-year survival between LBVI-positive and LBVI-negative tumors (39.6% vs 54.8%, P = 0.006). Overall 5-year survival rates in each group were 58.8% (I), 45.8% (II), 45.7% (III) and 36.9% (IV), and there was a significant difference in overall survival between the four groups (P = 0.009). Multivariate analysis in stage II gastric cancer patients revealed that LBVI independently affected patient prognosis in LN-negative patients (P = 0.018) but not in LN-positive patients (P = 0.508). CONCLUSION: In LN-negative stage II gastric cancer patients, LBVI is an additional independent prognostic marker, and may provide useful information to identify patients with poorer prognosis.

Survival after anatomic resection versus nonanatomic resection for hepatocellular carcinoma: a meta-analysis.

BACKGROUND AND OBJECTIVES: To compare the effect on survival of anatomic resection (AR) versus nonanatomic resection (NAR) in patients with hepatocellular carcinoma (HCC) from all published comparative studies in the literature. METHODS: Databases, including Pubmed, Embase, the Cochrane Library, Ovid, and Web of Science, were searched to identify studies comparing AR with NAR for HCC. In this meta-analysis, primary end points were the overall survival and disease-free survival; the secondary end point was local recurrence rate. The meta-analysis was performed by use of RevMan 4.2. RESULTS: Nine comparative studies comprising 1,503 patients (833 AR and 670 NAR) were identified. In the combined results, disease-free survival was significantly higher in the AR group than in the NAR group (OR 1.78, 95% CI 1.22-2.59, P = 0.003; heterogeneity P = 0.08). Overall survival (OR 1.31, 95% CI 0.92-1.85, P = 0.13; heterogeneity P = 0.04) did not suggest any significant difference between AR and NAR. No statistically significant difference was found for local recurrence rate between the two resection methods (OR 0.55, 95% CI 0.25-1.23, P = 0.15; heterogeneity P = 0.010). CONCLUSIONS: Anatomic resection is associated with better disease-free survival than nonanatomic resection. Because heterogeneity was detected, caution is needed in interpretation of the results. Better designed, adequately powered studies are required to address this issue.

Simultaneous vs. staged resection for synchronous colorectal liver metastases: a metaanalysis.

PURPOSE: The optimal timing of surgical resection for synchronous colorectal liver metastases (SCLMs) remains controversial. The aim of this metaanalysis was to compare outcomes between simultaneous resection and staged resection from all published comparative studies in the literature. MATERIALS AND METHODS: Databases, including PubMed, Embase, Cochrane Library, Ovid, and Web of Science, were searched to identify studies comparing outcomes following simultaneous resection with staged resection for SCLM. The metaanalysis was performed by RevMan 4.2. RESULTS: Fourteen comparative studies comprising 2,204 patients were identified. Patients undergoing simultaneous resection were found to have similar operative time (weighted mean difference [WMD], -34.19; 95% confidence interval [CI], -81.32-12.95, P = .16) and intraoperative blood loss (WMD, -161.33; 95% CI, -351.45-28.79, P = .10). Shorter hospital stay (WMD, -4.77; 95% CI, -7.26-2.28, P < .01) and lower morbidity rate (odds ratio [OR], 0.71; 95% CI, 0.57-0.88, P = .002) were observed in simultaneous resection group. The survival rate in the simultaneous resection group did not statistically differ with that in the staged resection group at 1 year (OR, 0.77; 95% CI, 0.51-1.16, P = .21), 3 years (OR, 1.12; 95% CI, 0.85-1.47, P = .43), and 5 years (OR, 1.14; 95% CI, 0.86-1.50, P = .37) postresection, respectively. CONCLUSIONS: Simultaneous resection is safe and efficient in the treatment of patients with SCLM while avoiding a second major operation. In appropriately selected patients, simultaneous resection might be considered as the preferred treatment. Since heterogeneity was detected, caution is needed in interpretation of the results. Better designed, adequately powered studies are required for addressing this issue.

[Value of preoperative barium contrast examination for the diagnosis and operative planning in gastric cancer].

OBJECTIVE: To investigate the value of preoperative barium contrast examination for the diagnosis and operative planning in gastric cancer. METHODS: Clinical data of 229 gastric cancer patients were analyzed retrospectively. Lesions were divided into three parts: the cardiac, the body, and the antrum. The diagnostic accuracy of localization and the extent of tumor between gastroscopy alone and gastroscopy plus barium contrast were compared with the results of surgical findings. RESULTS: The diagnostic accuracy of localization and the extent of tumor for gastroscopy in the cardiac, the body and the antrum cancers were 100% and 78.4%, 94.6% and 86.5%, 98.1% and 84.6%, respectively, while for gastroscopy plus barium contrast were 100% and 84.8%, 100% and 91.9%, 99.0% and 90.4%, respectively. The diagnostic accuracy of both the localization and the extent of tumor were not significantly different between gastroscopy alone and gastroscopy plus barium contrast (P>0.05). Diagnostic accuracy of the length of esophagus infiltrated by cardiac cancer in gastroscopy was 60.6%, while in gastroscopy plus barium contrast was 90.9%, which was significantly different (P<0.05). Gastroscopy plus barium contrast was more accurate in predicting the possibility of thoracotomy in cardiac cancer infiltrating the lower esophagus. CONCLUSIONS: It is necessary to perform preoperative barium contrast examination in cardiac cancer patients, so as to identify whether the lower esophagus is infiltrated and to measure the length of lesion, which can provide evidences for making a decision of thoracotomy. For gastric body and antrum cancer, there is no indication for barium contrast examination if gastroscopy findings are satisfied.

Prognostic significance of c-erbB-2 and vascular endothelial growth factor in colorectal liver metastases.

BACKGROUND: The prognostic value of c-erbB-2 and vascular endothelial growth factor (VEGF) expression in colorectal liver metastases (CLM) is unclear. The purpose of this study was to clarify the relationship of c-erbB-2 and VEGF with the clinicopathological parameters and the survival results in CLM. METHODS: For 44 patients who had undergone liver resection for CLM at Fudan University Cancer Hospital from 2000 to 2007, the expression of c-erbB-2 and VEGF in CLM and the corresponding primary cancer specimens were evaluated immunohistochemically. The correlations among c-erbB-2 and VEGF, clinicopathologic factors, and survival were then statistically analyzed. RESULTS: Positive expression rates of c-erbB-2 and VEGF in CLM lesions were 38.64% and 52.72%, respectively. The expression of c-erbB-2 and VEGF in CLM were similar to that of corresponding primary tumor. c-erbB-2 expression correlated with number of metastatic lesions and the distribution of liver metastases. The expression of VEGF correlated with the size of liver metastatic lesion and distribution of liver metastases. A statistically significant association between the expression of c-erbB-2 and VEGF in both CLM and primary tumor was noted. Univariate analysis showed that VEGF was a prognostic factor. However, on multivariate analysis, expression of VEGF was not an independent prognostic marker. Patients with both negative expression of c-erbB-2 and VEGF expression had a better outcome than others. CONCLUSIONS: VEGF might be a statistically significant prognostic factor. The combined analysis of c-erbB-2 and VEGF is of added prognostic value. An association exists between c-erbB-2 and VEGF. However, further studies are required to confirm this issue.