LncRNA FAM225B Regulates PDIA4-Mediated Ovarian Cancer Cell Invasion and Migration via Modulating Transcription Factor DDX17.

Objective: This study aimed to explore the roles and mechanisms of lncRNA FAM225B and PDIA4 in ovarian cancer. Methods: RT-qPCR and Western blot assays were performed to detect the expression levels of the lncRNAs FAM225B, DDX17, and PDIA4 in the serum of patients with ovarian cancer and cell lines. Cells were transfected with lncRNA FAM225B- and PDIA4-related vectors to determine the malignant phenotypes using functional experiments. The mutual binding of lncRNA FAM225B and DDX17 was verified using RNA pull-down and RIP assays. Results: The expression of lncRNAs FAM225B and PDIA4 was decreased in the serum of patients with ovarian cancer and cell lines. Restoration of lncRNA FAM225B or PDIA4 reduced cell proliferation, migration, and invasion abilities and elevated the apoptosis rate, whereas suppression of lncRNA FAM225B or PDIA4 exhibited an inverse trend. RNA pull-down and RIP assays revealed a direct interaction between lncRNA FAM225B and DDX17. ChIP assay revealed a relationship between DDX17 and the PDIA4 promoter. LncRNA FAM225B and DDX17 positively regulate PDIA4 expression. Downregulation of PDIA4 expression counteracts the suppressive effect of lncRNA FAM225B overexpression in ovarian cancer cells. Conclusion: This research study supports the fact that lncRNA FAM225B in ovarian cancer can upregulate PDIA4 by directly binding to DDX17, inhibiting the activities of ovarian cancer cells.

Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.

OBJECTIVE: An early onset of menarche and, later, menopause are well-established risk factors for the development of breast cancer and endometrial cancer. Although the largest GWASs have identified 389 independent signals for age at menarche (AAM) and 44 regions for age at menopause (ANM), GWAS can only identify the associations between variants and traits. The aim of this study was to identify genes whose expression levels were associated with AAM or ANM due to pleiotropy or causality by integrating GWAS data with genome-wide expression quantitative trait loci (eQTLs) data. We also aimed to identify the pleiotropic genes that influenced both phenotypes. METHOD: We employed GWAS data of AAM and ANM and genome-wide eQTL data from whole blood. The summary data-based Mendelian randomization method was used to prioritize the associated genes for further study. The colocalization analysis was used to identify the pleiotropic genes associated with both phenotypes. RESULTS: We identified 31 genes whose expression was associated with AAM and 24 genes whose expression was associated with ANM due to pleiotropy or causality. Two pleiotropic genes were identified to be associated with both phenotypes. CONCLUSION: The results point out the most possible genes which were responsible for the association. Our study prioritizes the associated genes for further functional mechanistic study of AAM and ANM and illustrates the benefit of integrating different omics data into the study of complex traits.

Celecoxib suppresses proliferation and metastasis of pancreatic cancer cells by down-regulating STAT3 / NF-kB and L1CAM activities.

OBJECTIVE: To explore the molecular mechanisms of celecoxib-induced pancreatic cancer suppression in vivo and in vitro. METHODS: The anti-pancreatic cancer activities of celecoxib (0, 20, 60 and 100 µmol/L) were investigated by cell viability and migration of Panc-1 and Bxpc-3 cells in vitro. The expression of L1CAM in pancreatic cancer and adjacent tissues was compared using immunohistochemistry. The expressions of L1CAM, STAT3, p-STAT3, NF-κB, p-NF-κB were determined by western blotting, and cell invasive ability was determined by wound healing assay in L1CAM-silenced and over-expressed Panc-1and Bxpc-3 cells. RESULTS: The expression of L1CAM in pancreatic carcinoma was stronger than that in the adjacent tissues and L1CAM could increase the growth and invasion of pancreatic cancer cells. Over-expression of L1CAM activated the STAT3/NF-κB signaling pathway in Panc-1 and Bxpc-3 pancreatic cancer cells and celecoxib inhibited their viability and the expressions of STAT3, p-STAT3, NF-κB, p-NF-κB as well as full length L1CAM in a concentration dependent manner. CONCLUSIONS: L1CAM was highly expressed in pancreatic cancer tissue and positively correlated with age, TNM staging and tumor differentiation. L1CAM activated the STAT/NF-κB signaling pathway and celecoxib could inhibit the activity of L1CAM, STAT3 and the NF-κB signaling pathway resulting in decreased growth and invasion of pancreatic cancer cells.

Ack1 overexpression promotes metastasis and indicates poor prognosis of hepatocellular carcinoma.

Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection. Ack1 promoted HCC invasion and metastasis in vitro and in vivo. Mechanistically, we confirmed that Ack1 enhanced invasion and metastasis of HCC via EMT by mediating AKT phosphorylation. In conclusion, our study shows Ack1 is a novel prognostic biomarker for HCC and promotes metastasis of HCC via EMT by activating AKT signaling.

Clavien-Dindo classification and risk factors of gastrectomy-related complications: an analysis of 1049 patients.

OBJECTIVE: The objective of the present study was to explore the major risk factors of surgical complications using the Clavien-Dindo classification. METHODS: The case-control design was used. A total of 1049 patients who underwent radical gastrectomy in Hunan Cancer Hospital between October 2010 and August 2014 were retrospectively analyzed, including 122 patients (11.6%) with complications and 927 patients (88.4%) with no complications. Risk factors were evaluated. RESULTS: Following radical gastrectomy, 122 patients (11.6%) experienced a total of 151 complications. The incidence of Stages II, IIIa, IIIb, IVa, IVb and V complications was 9.6% (n = 101), 2.5% (n = 26), 1.0% (n = 11), 0.8% (n = 8), 0% (n = 0), and 0.5% (n = 5), respectively. The incidence of severe complications (Stage ≥ IIIa) was 4.8% (n = 50). Multivariate analysis showed that combined resection (Odds Ratio [OR] = 3.36, 95% confidence interval [CI]: 1.71~6.60, P < 0.01), perioperative blood transfusion (OR = 2.13, 95% CI: 1.38-3.29, P < 0.01), and BMI ≥ 25 kg/m(2) (OR = 1.98, 95% CI: 1.16-3.40, P = 0.01) were independent risk factors of complications. CONCLUSIONS: Combined resection, perioperative blood transfusion, and BMI ≥ 25 kg/m(2) are positively correlated with complications.

Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in the prevention and treatment of HCC, but it remains controversial as to whether IFN-α exerts direct cytotoxicity against HCC. Cyclooxygenase-2 (COX-2) is overexpressed in HCC and is considered to play a role in hepatocarcinogenesis. Therefore, we aimed to elucidate the combined effect of a COX-2 inhibitor, celecoxib, and IFN-α on in vitro growth suppression of HCC using the hepatoma cell line HLCZ01 and the in vivo nude mouse xenotransplantation model using HLCZ01 cells. Treatment with celecoxib and IFN-α synergistically inhibited cell proliferation in a dose- and time-dependent manner. Apoptosis was identified by 4׳,6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-α upregulated the expression of TRAIL, while celecoxib increased the expression of TRAIL receptors. The combined regimen with celecoxib and IFN-α reduced the growth of xenotransplanted HCCs in nude mice. The regulation of IFN-α- and COX-2 inhibitor-induced cell death is impaired in a subset of TRAIL-resistant cells. The molecular mechanisms of HCC cells resistant to TRAIL-induced apoptosis were explored using molecular biological and immunological methods. Interferon-α and the COX-2 inhibitor celecoxib synergistically increased TRAIL-induced apoptosis in hepatocellular carcinoma. These data suggest that IFN-α and celecoxib may offer a novel role with important implications in designing new therapeutics for TRAIL-resistant tumors.

Transcatheter arterial chemoembolization combined with interferon-α is safe and effective for patients with hepatocellular carcinoma after curative resection.

OBJECTIVES: Intrahepatic recurrence is the major cause of death among patients with hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC) after curative surgical resection. Several approaches have been reported to decrease the recurrence rate. The objective of our study was to compare the clinical effects of transcatheter arterial chemoembolization (TACE) combined with interferon-alpha (IFN-α) therapy on recurrence after hepatic resection in patients with HBV-related HCC with that of TACE chemotherapy alone. METHODS: We retrospectively analyzed the data from 228 patients who were diagnosed with HBV-related HCC and underwent curative resection between January 2001 to December 2008. The patients were divided into TACE (n = 126) and TACE-IFN-α (n = 102) groups for postoperative chemotherapy. The TACE regimen consisted of 5-fluorouracil (5-FU), cisplatin (DDP) , and the emulsion mixed with mitomycin C (MMC) and lipiodol. The recurrence rates, disease-free survival (DFS), overall survival (OS), and risk of recurrence were evaluated. RESULTS: The clinicopathological parameters and adverse effects were similar between the 2 groups (P > 0.05). The median OS for the TACE- IFN-α group (36.3 months) was significantly longer than that of the TACE group (24.5 months, P < 0.05). The 3-and 5-year OS for the TACE-IFN-α group were significantly longer than those of the TACE group (P < 0.05) and the recurrence rate was significantly lower (P < 0.05). The TACE and IFN-α combination therapy, active hepatitis HBV infection, the number of tumor nodules, microvascular invasion, liver cirrhosis, and the BCLC stage were independent predictors of OS and DFS. CONCLUSIONS: The use of the TACE and IFN-α combination chemotherapy after curative hepatic resection safely and effectively improves OS and decreases recurrence in patients with HBV-related HCC who are at high risk. Our findings can serve as a guide for the selection of postoperative adjuvant chemotherapy for patients with HBV-related HCC who are at high risk of recurrence.

ISG15 as a novel prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-α) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. IFN-stimulated gene 15 (ISG15) is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Several studies have shown that the overexpression of ISG15 is correlated with multiply tumor types. However, the role of ISG15 in hepatitis B virus (HBV)-related HCC remains undetermined. ISG15 expression was found to be obviously higher in HBV-related HCC tissues than that in non-tumor tissues. ISG15 is a novel prognostic marker for predicting 5-year overall survival of HBV-related HCC patients. Overexpression of ISG15 was associated with clinicopathological characteristics and poor patient outcomes. ISG15 may serve as a novel prognostic marker for HBV-related HCC. Therefore, ISG15 may represent a novel HCC marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of HBV-related HCC.

Characterization of lymph node metastasis and its clinical significance in the surgical treatment of gastric cancer.

This study aimed to characterize lymph node metastasis and determine its clinical significance in the surgical treatment of gastric cancer. The medical charts of 920 gastric cancer patients who underwent radical surgical resection between March, 2010 and March, 2013, were retrospectively reviewed and statistically analyzed. Lymphatic metastasis was observed in 69.6% of the patients (640/920). The frequency of lymph node metastasis in patients with early-stage gastric cancer was 21.4% (18/84). Lymph node metastasis was observed in all the patients with stage IIIC-IV gastric cancer. The incidence of lymph node metastasis was higher among patients with tumors >7 cm in size. The most frequently affected lymph nodes in patients with proximal, central and distal gastric cancer were station no. 1 (34.2%), no. 3 (33.8%) and no. 6 (34.3%) lymph nodes, respectively. The frequency of lymph node metastasis in patients with Borrmann type IV cancer was significantly higher compared to that in patients with other Borrmann type cancers. Our study further demonstrated that lymphatic metastasis is closely correlated with TNM stage, location, depth of invasion and size of gastric tumors. Therefore, we recommend that a sufficient number of lymph nodes be examined from each patient to determine the extent of lymph node dissection based on Borrmann type, location, size, depth of invasion and histology of the cancer.

Mesohepatectomy for the treatment of patients with centrally located hepatocellular carcinoma.

Mesohepatectomy is considered a feasible option for patients with centrally located hepatocellular carcinoma (HCC). However, mesohepatectomy is a technically demanding and less frequently used procedure. In this study, we summarized the surgical experience and evaluated the clinical outcomes of mesohepatectomy in 24 patients with centrally located HCC. Of these patients, 9 were treated with hepatectomy of Couinaud's segments IV, V and VIII with concurrent cholecystectomy; 8 underwent resection of segments IVb, V and VIII, including 7 patients who also received a cholecystectomy; 4 underwent hepatectomy of segments IVa, V and VIII; and 3 patients were treated with hepatectomy of segments I, IV, V and VIII, with concurrent cholecystectomy. The Pringle maneuver was used on 17 patients during hepatectomy. Total hepatic vascular exclusion (HVE) was performed on 3 patients and HVE was not used on 4 patients. The average mesohepatectomy operative time was 238 min and the average intraoperative blood loss was 480 ml (200-2,200 ml). There was no intraoperative mortality and the postoperative morbidity rate was 25% (6/24). The 1- and 3-year overall survival rates were 76 and 46%, respectively. Therefore, mesohepatectomy is a safe and effective surgical procedure for the treatment of centrally located HCC and HVE during mesohepatectomy for centrally located HCC is crucial to the success of the operation and postoperative patient recovery.

[Association of perioperative transfusion and postoperative complications after radical gastrectomy for gastric cancer].

OBJECTIVE: To explore the association of perioperative homologous blood transfusion (packed red blood cell, PRBC) and postoperative complications after radical gastrectomy in patients with gastric cancer. METHODS: From October 2010 to July 2013, a total of 636 patients undergoing radical gastrectomy at Department of Gastric, Duodenal & Pancreatic Surgery at Hunan Provincial Tumor Hospital were divided into 2 groups according to perioperative blood transfusion (n = 170, 26.73%) or not (n = 466, 73.27%). Their clinicopathological data, such as age, gender, co-morbidities, surgical duration, intraoperative blood loss volume and pathological stage were retrospectively analyzed by case-control study model. And the transfusion group was further divided into subgroup by transfusion volume (total PRBC<3.0, 3.0-7.5 or >7.5 U) and timing (pre-, intra- or post-operative) to examine the association of transfusion volume and timing with postoperative complications by Logistic regression. RESULTS: Thirty-two patients suffered from complications in the transfusion group (18.82%). And it was significantly more common than that in the control group (10.09% (47/466) , P < 0.01). Moreover, the complication rate (33.33% (12/36) ) was obviously higher in the large transfusion volume group (PRBC>7.5 U) than with those in the moderate (15.53% (16/103), P = 0.02) and low groups (12.90% (4/31) , P = 0.04). Infection was more common along with the total amount of transfused blood (6.45% (2/31), 10.68% (11/103) and 19.44% (7/36) in the low, moderate and large transfusion group respectively). Yet the differences were insignificant (P = 0.22). There was no significant difference of complication rates among the pre-, intra- and post-operative transfusion group classified by transfusion time (P = 0.39). And the postoperative infection rates were also insignificantly different (P = 0.88). Further Logistic analysis revealed that perioperative transfusion (OR = 2.71, 95% CI: 1.40-5.27, P < 0.01) was an independent risk factor for postoperative complications after radical gastrectomy. CONCLUSIONS: Perioperative blood transfusion is significantly associated with postoperative complications after radical gastrectomy in patients with gastric cancer. And a positive correlation exists between infection and the amount of transfused blood. But there was no association between transfusion time and complications. Thus decreasing perioperative transfusion may reduce the incidence of postoperative complications and shorten the length of hospital stays.

[Multivariate analysis of risk factors for pulmonary infection after radical gastrectomy for gastric cancer].

OBJECTIVE: To explore the major risk factors for pulmonary infection after radical gastrectomy in patients with gastric cancer. METHODS: From November 2010 to February 2014, a total of 765 patients undergoing radical gastrectomy at our hospital were divided into 2 groups based upon the presence of postoperative pulmonary infection (n = 32, 4.2%) or not (n = 733, 95.8%). Their clinicopathological data were retrospectively analyzed by Logistic regressive analysis with a case-control study model. RESULTS: Comparing with the control group, the patients had longer surgical duration (245.7 ± 66.7 vs 210.9 ± 47.2 min, P < 0.01), higher rates of requiring intensive care (12.50% vs 2.86%, P = 0.02) and longer post-operative hospital stays (21.9 ± 24.9 vs 14.2 ± 4.2 days, P < 0.01) in the postoperative pulmonary infection group.Univariate Logistic regressive analysis found that age ≥ 60 years, smoking ≥ 400 year by cigarette, diabetes mellitus, chronic obstructive pulmonary disease, proximal or total gastrectomy, combined organ resection, surgical duration ≥ 240 min, intra-operative blood loss ≥ 300 ml, peri-operative transfusion, transfusion ≥ 3 unit packed red blood cell, post-operative transfusion and post-operative complications other than pulmonary infections were associated with postoperative pulmonary infection (all P < 0.05).Further multivariate analysis identified 4 independent risk factors for pulmonary infection after radical gastrectomy, including diabetes mellitus (OR = 4.77, 95%CI:1.18-19.23), post-operative complications other than pulmonary infections (OR = 3.15, 95%CI:1.25-7.90), intra-operative blood loss ≥ 300 ml (OR = 2.63, 95%CI:1.17-5.90) and post-operative nasogastric tube ≥ 5 days (OR = 2.30, 95%CI:1.02-5.21). CONCLUSION: Correcting the modifiable risk factors may reduce the incidence of pulmonary infection and shorten the length of hospital stays and costs after radical gastrectomy in patients with gastric cancer.

[Multivariate analysis of risk factors for intra-abdominal infections after radical gastrectomy for gastric cancer].

OBJECTIVE: To explore the major risk factors for intra-abdominal infections after radical gastrectomy in patients with gastric cancer. METHODS: From October 2010 to January 2013, a total of 479 patients undergoing radical gastrectomy at Department of Gastric, Duodenal & Pancreatic Surgery, Hunan Provincial Tumor Hospital were divided into 2 groups according to an onset of postoperative intra-abdominal infections (n = 32, 6.68%) or not (n = 447, 93.32%). Their clinicopathological data, such as age, gender, co-morbidities, surgical duration, operative blood loss and pathological stage were retrospectively analyzed by Logistic regressive analysis with a case-control study model. RESULTS: As compared with the control group, the patients had a greater age ((59 ± 10) vs (53 ± 11) years, P < 0.01), lower lymphocyte count ((1.4 ± 0.7) ×10(9)/L vs (1.7 ± 0.6) ×10(9)/L, P = 0.02), lower hemoglobin level ( (108 ± 28) vs (117 ± 24) g/L, P = 0.04), lower albumin level ((34 ± 6) vs (37 ± 5) g/L, P < 0.01) and longer surgical duration ((244 ± 43) vs (216 ± 45) min, P < 0.01) in the postoperative intra-abdominal infection group. Univariate Logistic regressive analysis found that a history of abdominal surgery, body mass index (BMI) >25 kg/m(2), co-morbidities, diabetes mellitus, complications due to gastric cancer, lymphocyte count <1.5×10(9)/L, hemoglobin <100 g/L, albumin <30 g/L, ascites, perioperative transfusion, total mastectomy, combined organ resection and surgical duration >240 min were associated with the occurrence of postoperative intra-abdominal infections (all P < 0.05). Further multivariate analysis identified 4 independent risk factors for intra-abdominal infections after radical gastrectomy, including combined multiorgan resection (OR = 3.64, 95%CI: 1.39-9.55), BMI>25 kg/m(2) (OR = 3.04, 95%CI: 1.17-7.92), diabetes mellitus (OR = 3.41, 95%CI: 1.05-11.09) and perioperative transfusion (OR = 2.24, 95%CI: 1.02-5.13). CONCLUSION: A correction of modifiable risk factors may reduce the incidence of intra-abdominal infections after radical gastrectomy, shorten the length of hospital stays and improve outcomes in patients with gastric cancer.

[Clavien-Dindo classification and risk factors for complications after radical gastrectomy for gastric cancer].

OBJECTIVE: To explore the complications after radical gastrectomy in patients with gastric cancer according to Clavien-Dindo classification and examine the major risk factors for complications. METHODS: From October 2010 to June 2013, a total of 614 patients undergoing radical gastrectomy at Department of Gastric,Duodenal & Pancreatic Surgery at Hunan Provincial Tumor Hospital were divided into 2 groups according to the occurrence of complications (n = 76, 12.38%) or not (n = 538, 87.62%). Their clinicopathological data, such as age, gender, co-morbidities, surgical duration, operative blood loss volume and pathological stage were retrospectively analyzed by Logistic regression with a case-control model. RESULTS: Among them, 76 patients developed complications (12.38%). According to Clavien-Dindo classification, 56(9.12%), 14(2.28%), 3(0.49%) and 3(0.49%) patients suffered stage II, III, IV and V complications respectively. Comparing with the control group, the patients had a higher transfusion rate (43.42% (n = 33) vs 24.16% (n = 130), P < 0.01) and a longer postoperative hospital stay in the complication group ((23 ± 18) vs (14 ± 6) days, P < 0.01). There was no difference in age, gender, body mass index (BMI), number of dissected lymph node, levels of hemoglobin and albumin at admission, intraoperative hemorrhage, surgical duration and pathological TNM stage in two groups (all P > 0.05). Univariate analysis revealed that BMI > 25 kg/m(2), co-morbidities, diabetes mellitus, complications due to gastric cancer, hemoglobin <100 g/L, albumin <30 g/L, ascites, total gastrectomy, combined multi-organ resection, surgical duration >240 min and perioperative transfusion were associated with postoperative complications (all P < 0.05).Further multivariate analysis showed that perioperative transfusion (OR = 2.78, 95%CI: 1.42-5.43, P < 0.01) and combined multi-organ resection (OR = 1.72, 95%CI: 1.14-2.58, P = 0.01) were independent risk factors for postoperative complications after radical gastrectomy. CONCLUSIONS: Classifying the complications after radical gastrectomy according to Clavien-Dindo classification is important for comparisons and quality assessments among different studies. And decreasing perioperative transfusion and avoiding combined multi-organ resection may reduce the incidence of postoperative complications and shorten the length of hospital stay.