Association Between EphA1 and Tumor Microenvironment in Gastric Carcinoma and its Clinical Significance.

BACKGROUND With the growing global burden of gastric carcinoma (GC) and the urgent need for biomolecular targeted therapies, this study aimed to elucidate the relationship between EphA1 and the tumor microenvironment (focusing primarily on the key inflammatory cytokines IL-6 and tumor angiogenic cytokine VEGF) to identify a new potential therapeutic target. MATERIAL AND METHODS IHC and qRT-PCR were performed to quantify the protein and gene expression levels of EphA1, IL-6, and VEGF in normal mucosal tissues, carcinoma tissues, and paracarcinomatous tissues from 57 GC patients. Spearman's rank correlation test was performed to determine the relationship between EphA1, IL-6, and VEGF expression levels. The relationships of EphA1 with clinicopathologic parameter and survival in GC patients were also evaluated. RESULTS The protein and gene expression levels of EphA1 were all attenuated gradually from carcinoma tissues to paracarcinomatous tissues and then to normal mucosal tissues in GC patients. Additionally, significant correlations between the overexpression of EphA1 with aggressive clinicopathological features and shorter survival time of GC patients were verified. In particular, we found a significant positive correlation between the expression of EphA1 and tumor microenvironment hallmark proteins IL-6 and VEGF in carcinoma tissues and paracarcinomatous tissues. CONCLUSIONS EphA1 can promote the occurrence and development of GC by its selective high expression in cancer tissues and its relationship with malignant clinical features and prognosis of GC patients. The underlying potential mechanism appears to involve enhancement of the tumor microenvironment, which via drives the expression of tumor microenvironment hallmark proteins IL-6 and VEGF.

Perioperative analgesia with parecoxib sodium improves postoperative pain and immune function in patients undergoing hepatectomy for hepatocellular carcinoma.

RATIONALE, AIMS, AND OBJECTIVES: Acute postoperative pain can result in immune dysfunction, which can be partly mitigated by efficient pain management. Opioids that have been widely applied to analgesia have been shown to suppress immune function, which has a negative impact on the treatment of patients with cancer. This study investigated the effects of perioperative fentanyl analgesia alone or in combination with parecoxib sodium on postoperative pain, immune function, and prognosis in patients undergoing hepatectomy of hepatocellular carcinoma (HCC). METHODS: A total of 80 patients scheduled for hepatectomy between October 2013 and August 2014 were included. Patients were randomly divided into two groups (n = 40) and allocated to receive parecoxibsodium 40 mg (group P) or placebo (group C) 30 minutes before induction of anaesthesia, followed by 40 mg every 12 hours for 48 hours after the operation. All patients had access to patient-controlled analgesia with intravenous fentanylpostoperatively. Venous blood samples were collected at the following time points: 30 minutes before induction of anaesthesia (T0), the end of the surgery (T1), 24 hours after surgery (T2), and 72 hours after surgery (T3). The percentages of CD3+, CD4+, CD8+, CD4+/CD8+ T cells, and CD3+CD16+CD56+ (NK) cells at these time points were quantified by flow cytometry (FCM).Visual analogue scale (VAS) scores, total fentanyl consumption, and adverse effects were recorded. The prognostic differences in overall survival (OS) and disease-free survival (DFS) between the two groups was also investigated. RESULTS: For both groups, the percentages of CD3+, CD4+ T cells, and the ratio of CD4+/CD8+ significantly decreased at T1 and T2 (P < .05). The percentages of CD3+ T cells were significantly lower in group C than that in group P at T2 (P < .05). In group C, the amount of CD3+ T cells was lower at T3 compared with T0 (P < .05). The percentages of NK cells significantly decreased at T1 in both groups (P < .05). The percentages of NK in group P were recovered nearly to baseline (T0) at T2, which was higher than that of group C (P < .05). In group C, the percentages of NK cells have not recovered nearly to baseline at T3 compared with T0 (P < .05). VAS scores at rest and on cough in group P were significantly lower than those in group C at 2, 6, 12, and 24 hours after operation (P < .05), and there were no significant differences in VAS scores between the two groups at 48 hours after surgery (P > .05). There were no significant differences regarding the incidence of adverse effects between the two groups (P > .05). Kaplan-Meier analysis indicated that the DFS time in group P was significantly longer than in group C (19.0 months, 95% confidence interval [CI], 9.8-28.2 vs 14.0 months, 95% CI, 8.1-19.9; P < .05). There was no significant difference in OS time (36.0 months, 95% CI, 13.4-58.9 vs 14.0 months, 95% CI, 10.6-25.4; P > .05) between two groups. CONCLUSIONS: The present study indicated that perioperative analgesia of parecoxib sodium combined with patient-controlled analgesic fentanyl resulted in better preserved immune function with enhancement of the analgesic efficacy to fentanyl alone of HCC patients undergoing hepatectomy and helped postpone postoperative tumour recurrence.

Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial.

OBJECTIVE: There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. DESIGN AND RESULTS: A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively. CONCLUSIONS: This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. TRIAL REGISTRATION: NCT01770431; Post-results.

Knockdown of GTPBP4 inhibits cell growth and survival in human hepatocellular carcinoma and its prognostic significance.

GTP-binding protein 4 (GTPBP4), as a novel member of GTPases involved in the synthesis of 60S subunit and maturation, is closely related to cell proliferation and growth. Till now, a small number of existing studies have found a contradictory dual role of GTPBP4 in cancer. Whether the expression level of GTPBP4 in hepatocellular carcinoma (HCC) is associated with the patients' prognosis or its function and underlying molecular mechanisms still remains unclear. In the present study, the above issues were explored for the first time. Our results showed that GTPBP4 was overexpressed in HCC and knockdown of GTPBP4 delayed cell proliferation, impaired colony formation ability, induced cell cycle arrest in G2/M period and promoted apoptosis in HCC cell lines. Besides, in vivo xenograft nude mice model revealed that GTPBP4 knockdown could significantly suppress HCC tumorigenesis. Gene microarray and further pathway enrichment analyses indicated that ERBB signaling pathway was the most significantly changed one. More importantly, high GTPBP4 expression level significantly correlated to the poor prognosis of HCC patients. Taken together, all these findings suggest that GTPBP4 serves as an oncogene and plays a pivotal role in HCC development, which will be a potential therapeutic target or a biomarker for HCC.

Overexpression of Acyl-CoA Ligase 4 (ACSL4) in Patients with Hepatocellular Carcinoma and its Prognosis.

BACKGROUND Recently, accumulating studies have found that ACSL4 dysregulation is related to a great number of malignant tumors. The purpose of the present study was to explore the relationship between ACSL4 expression level and clinical prognosis of hepatocellular carcinoma (HCC) patients. MATERIAL AND METHODS The Oncomine and TCGA databases were used to predict the expression of ACSL4 mRNA in HCC and its association with HCC prognosis. Further, immunohistochemistry was performed to verify the ACSL4 protein expression in 116 paired HCC and adjacent normal tissues. Kaplan-Meier and cox analysis were performed to validate the correlation between ACSL4 expression and HCC prognosis. RESULTS We first used the Oncomine database to find that ACSL4 mRNA expression level was significantly higher in HCC tissues than that in normal tissues (p all <0.001). The results were consistent with those in the TCGA database. Then, immunohistochemical results demonstrated that the ACSL4 positive expression rate was 70.7% in HCC tissues. ACSL4 differential expression level was significantly related to Edmondson grade (p=0.010), AFP (p=0.001) and TNM stage (p=0.012). Survival analysis revealed that both overall survival (OS) and disease-free survival (DFS) time were remarkably reduced in HCC patients with ACSL4 high expression (p=0.001 and 0.000, respectively). Moreover, Cox multivariate analysis demonstrated that ACSL4 expression was the only independent prognostic factor for both OS and DFS (both p values=0.001). CONCLUSIONS Taken together, our study demonstrated that ACSL4 was overexpressed in HCC, and it will be a new potential therapeutic target for HCC as an independent adverse prognostic parameter.

A single-center experience of sorafenib monotherapy in patients with advanced intrahepatic cholangiocarcinoma.

Patients with advanced intrahepatic cholangiocarcinoma (ICC) have a poor prognosis and the therapeutic options available for treating ICC are limited. Sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet derived growth factor receptor-ß, B-Raf proto-oncogene, serine/threonine kinase and C-Raf proto-oncogene, serine/threonine kinase, is a novel reference standard for the treatment of advanced hepatocellular carcinoma. Sorafenib has previously been demonstrated to exhibit significant antitumor activity in various cholangiocarcinoma cell lines and in xenograft ICC models. The present study aimed to assess the efficacy and safety of sorafenib as a single-agent treatment in patients with advanced ICC. Eligible patients were administere no prior therapy for metastatic or unresectable disease. Sorafenib was administered orally at a dose of 400 mg twice daily continuously. The primary endpoint was considered as the disease control rate (DCR) at 12 weeks. Secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of treatment (DOT) and the adverse event profile. A total of 15 patients were enrolled in the present study, with a median DOT of 3.2 months (range, 1.5-30 months). A total of 4 patients achieved a partial response and 7 patients achieved stable disease, with a DCR of 73.3%. The median OS time was 5.7 months [95% confidence interval (CI), 5.0-6.4], the PFS time was 5.5 months (95% CI, 3.9-7.1) and the median TTP was 3.2 months (range, 1.5-29 months). The most common toxicity was a skin rash, which w1as observed in 5 patients (33.3%). Grade 3 hand-foot syndrome was observed in 1 patient (6.7%), which required treatment termination. The results of the present study suggest that sorafenib monotherapy may exhibit promising anticancer activity in patients with advanced ICC and that it has a manageable toxicity profile.

Prognostic value of polarized macrophages in patients with hepatocellular carcinoma after curative resection.

As the most predominant tumour-infiltrating immune cells, tumour-associated macrophages (TAMs) are significant for fostering tumour growth, progression and metastasis. CD68-positive TAMs display dissimilarly polarized programmes comprising CD11c-positive pro-inflammatory macrophages (M1) and CD206-positive immunosuppressive macrophages (M2). The aim of this study is to determine the prognostic significance of diametrically polarized TAMs in hepatocellular carcinoma (HCC) and their application to risk stratification of patients according to their specific prognostic values. This study included 80 consecutive patients with HCC, and we evaluated diametrically polarized functional status of macrophages by immunohistochemical staining of CD68, CD11c and CD206. Prognostic values and clinicopathologic features were assessed in these patients. High versus low CD11c-positive TAM density (P = 0.005) and low versus high CD206-positive TAM density (P = 0.002) were associated with better overall survival, whereas CD68-positive TAM density had no prognostic significance (low versus high, P = 0.065). Furthermore, the presence of these positive staining macrophages did not show any prognostic significance for recurrence-free survival (all P > 0.05). Multivariate Cox regression analysis identified CD11c-positive and CD206-positive TAMs as an independent prognostic factor (P < 0.001, P = 0.031, respectively). Intratumoural infiltration of diametrically polarized TAMs, a novel identified independent prognostic factor for survival in patients with HCC, could be combined with the TNM stage and the Barcelona Clinic Liver Cancer stage to improve a risk stratification system.

Kindlin-2: a novel prognostic biomarker for patients with hepatocellular carcinoma.

The association of aberrant expression of Kindlin-2 with tumor progression has been reported in recent years. The purpose of this study was to investigate the expression of Kindlin-2 in hepatocellular carcinoma (HCC), and to evaluate its clinical and prognostic significance. The mRNA and protein levels of Kindlin-2 in HCC and adjacent non-cancerous tissues were examined by real-time PCR and western blotting. The relationships between Kindlin-2 expression, clinicopathological features and postoperative survival of HCC patients were also evaluated. Kindlin-2 expression was higher in HCC tissues as compared to adjacent non-cancerous tissues at both mRNA and protein levels (P<0.05, respectively). Positive expression of Kindlin-2 was significantly correlated with larger tumor size (P=0.034), capsular invasion (P=0.009), microvascular invasion (P=0.028) and poor prognosis of HCC patients (P<0.001). Moreover, multivariate survival analysis identified Kindlin-2 as an independent prognostic factor for overall and disease-free survival of HCC patients (P=0.018 and 0.001, respectively). Taken together, our findings suggested that Kindlin-2 was highly expressed in HCC tissues and was closely related to clinical progression. Therefore, Kindlin-2 protein could be a potential biomarker for predicting poor prognosis of HCC patients after surgery.

Expression of Kindlin-1 in human hepatocellular carcinoma and its prognostic significance.

Kindlin-1 is a member of the Kindlin family of focal adhesion proteins and is implicated in cell adhesion, proliferation, polarity, and motility. Although expression of Kindlin-1 has recently been reported in a variety of human cancers, studies on its expression in human hepatocellular carcinoma (HCC) are currently lacking. This study aimed to determine the clinicopathological parameters and prognostic value of Kindlin-1 in HCC patients after surgical resection. The messenger RNA (mRNA) and protein levels of Kindlin-1 in 22 matched HCC specimens were assessed by quantitative real-time PCR (qRT-PCR) and Western blotting assays. The clinical and prognostic significance of Kindlin-1 in 68 cases of HCC was determined by immunohistochemistry. Kindlin-1 expression was higher in HCC tumor tissues relative to that in adjacent normal tissue at the both mRNA and protein levels (p < 0.05). Immunohistochemical results revealed that overexpression of Kindlin-1 was detected in 37 of 68 (54.4 %) tumor tissues and in seven of 68 (10.3 %) adjacent non-tumor tissues (p < 0.05). Positive Kindlin-1 expression was significantly correlated with tumor size, tumor capsula, status of metastasis, and tumor-node-metastasis (TNM) stage. Additionally, Kaplan-Meier survival analysis showed that positive Kindlin-1 expression was associated with unfavorable overall survival (OS) and disease-free survival (DFS). Multivariate analysis identified Kindlin-1 as an independent prognostic predictor for OS and DFS in HCC patients (p = 0.041 and 0.027, respectively). Taken together, our data suggest that Kindlin-1 could play an important role in HCC and might serve as a promising prognostic marker and potential target for HCC therapy.

Overexpression of HOXA13 as a potential marker for diagnosis and poor prognosis of hepatocellular carcinoma.

HOXA13 is a member of homeobox genes that encode transcription factors regulating embryonic development and cell fate. Abnormal HOXA13 expression was reported in hepatocellular carcinoma (HCC), but its correlation with tumor angiogenesis and prognosis still remain unclear. This study was aimed to uncover the expression, diagnostic and prognostic significance of HOXA13 in HCC. Immunohistochemistry was performed to detect HOXA13 expression in HCC and corresponding paracarcinomatous tissues from 90 patients. Enzyme-linked immunosorbent assay was used to detect serum HOXA13 in 90 HCC patients and 20 healthy volunteers. Receiver operating characteristics was analyzed to calculate diagnostic accuracy of serum HOXA13, alpha-fetoprotein (AFP) and their combination. Immunoreactivity of HOXA13 was detected in 72.2% of HCC, and 12.2% of adjacent non-cancerous samples. HOXA13 expression was significantly associated with tumor size, microvascular invasion, pathological grade, tumor capsula status, AFP level, tumor-node-metastasis stage and positively correlated with VEGF (p < 0.001) and microvessel density (p < 0.001). The combination of serum HOXA13 and AFP had a markedly higher area under the curve than HOXA13 alone. HOXA13 expression was associated with unfavorable overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001). Multivariate analysis indicated that patients with HOXA13-expressing tumors had a significantly shorter OS (p = 0.030) and DFS (p = 0.005) than those with HOXA13-negative tumors. Thus, HOXA13 expression possibly plays an important role in tumor angiogenesis, progression and prognosis of HCC. Moreover, we demonstrate that serum HOXA13 may serve as a biomarker for early HCC diagnosing and predicting outcome.

Aberrant estrogen receptor alpha expression correlates with hepatocellular carcinoma metastasis and its mechanisms.

BACKGROUND/AIMS: Metastasis one of the obstacles before poor prognosis of hepatocellular carcinoma (HCC) is improved. Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of HCC. However, the molecular mechanism of ERalpha in mediating HCC metastasis is still unclear. The aim of the present study was to detect aberrant ERalpha expression in HCC and elucidate its possible mechanisms in HCC metastasis. METHODOLOGY: We detected expression of ERalpha, phospho-estrogen receptor alpha (p-ERalpha), nuclear factor kappa B (NF-kappaB) p65 and Matrix metalloproteinase-9 (MMP-9) between HCC tissues with portal vein tumor thrombus (PVTT) and those without PVTT by immunohistochemical method. Moreover, the expression of above parameters was also determined in HCC cells of different metastatic potential by using immunocytochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. RESULTS: The expression of ERalpha and p-ERalpha was lower in HCC with PVTT than those without PVTT. Meanwhile, the expression pattern of above parameters was also similar in HCC cells of different metastatic potential, whereas, the expression of NF-kappaB p65 and MMP-9 was higher in HCC with PVTT than those without PVTT. The expression of NF-kappaB p65 and MMP-9 in HCC cells was also analogous to the tissues. CONCLUSIONS: These results demonstrated that expression of ERalpha, p-ERalpha, NF-kappaB p65 and MMP-9 correlated with invasion and metastasis in HCC. The mechanism of HCC metastasis may mediate through cross-talk between the NF-KB and ER signaling pathways. Meanwhile, ERa regulated MMP-9 through NF-kappaB indirectly.

Misdiagnosed gastrinoma: A case report.

Gastrinoma is most commonly located in the gastrinoma triangle (comprising of the duodenum, pancreas and bile ducts) or in the adjacent lymph nodes. Due to the low mortality rate, it is often misdiagnosed as other diseases with similar clinical characteristics, such as a solid pseudopapillary tumor of the pancreas (SPTP). Therefore, the current study reports a rare case of gastrinoma located in the tail of the pancreas of a female patient under medical examination, who exhibited no clinical symptoms. The tumor, which was located in the body and tail of the pancreas, was successfully resected and the spleen was preserved. The outcome of surgery combined with the postoperative pathological examination resulted in the patient being misdiagnosed with a SPTP. During the consequent six-year follow-up period, low-density liver lesions and an intractable peptic ulcer gradually appeared. Finally, the patient diagnosis was confirmed as a malignant pancreatic neuroendocrine carcinoma with liver metastases. On June 1, 2011, a liver transplant was successfully performed and the patient has maintained a good overall condition. The underlying clinical and pathological factors that may have resulted in misdiagnosis are investigated in the present study. Through providing our preliminary clinical experiences and lessons, the aim of the present study was to focus the attention of clinicians on this type of cancer in order to improve its diagnosis and treatment.

Protective effect of S-adenosylmethionine on hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic HBV infection.

BACKGROUND: Although hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S-adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis. METHODS: Eighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups. RESULTS: There were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-α between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients. CONCLUSIONS: Taken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis.

Embryonic morphogen nodal is associated with progression and poor prognosis of hepatocellular carcinoma.

BACKGROUND: Nodal, a TGF-ß-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial-mesenchymal transition, and prognosis is unclear. METHODS: We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters. RESULTS: Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC. CONCLUSIONS: Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis for HCC after surgery.

Overexpression of Mortalin in hepatocellular carcinoma and its relationship with angiogenesis and epithelial to mesenchymal transition.

Mortalin is highly expressed in a variety of human tumors and associated with tumor metastasis. However, the relationship among the overexpression of Mortalin, epithelial to mesenchymal transition (EMT) and neovascularization is largely unknown. The aim of the present study was to investigate the expression of Mortalin in human HCC cell lines, clinical HCC specimens and its association with angiogenesis and EMT. The results of our study showed that the expression levels of Mortalin in cell lines with higher metastatic potential were significantly higher compared to those with lower metastatic potential. Compared with paracarcinomatous tissues and normal liver tissues, the expression of Mortalin was significantly increased in HCC tumor tissues. The expression of Mortalin was correlated with invasion and metastasis, Edmondson grade and TNM stage. A significant positive correlation was found between the expression of Mortalin and Vimentin, and tumors with high expression of Mortalin had a tendency to higher MVD compared to those with low expression of Mortalin. Using shRNA-mediated Mortalin knockdown, we found that decreased expression of Mortalin was accompanied by a reduction of Vimentin expression. Our findings demonstrated that the overexpression of Mortalin is correlated with the metastatic phenotype of HCC cells and can promote EMT, but cannot induce angiogenesis in HCC. The decreased expression of Mortalin is accompanied by an inhibition of EMT in the HCC cell lines.

Anatomical right hemicolectomy: a novel surgical method and its clinical application.

BACKGROUND/AIMS: Presently, the notion of traditional right hemicolectomy has not met the rapidly developed requirements for precise gastrointestinal surgical procedures. In this study, we introduced a novel surgical method, namely "anatomical right hemicolectomy," and evaluated the safety and short-term effects of this method for the treatment of right hemicolon carcinoma. METHODOLOGY: The clinical data of 10 cases with progressive right hemicolon carcinoma underwent anatomical right hemicolectomy from January 2013 to February 2014 were collected and analyzed retrospectively. RESULTS: All the operations were successfully completed. The number of cleared lymph nodes was 18.0±6.7, the mean operative time was 162.7±25.3 mins, the mean blood loss was 95.2±32.5 ml, time to first flatus was 4.2±1.9 days, and the mean size of tumor was 4.96±3.2 cm. In these 10 patients, there was no case of respiratory infections, intestinal obstruction, anastomotic bleeding, anastomotic stricture, anastomotic leakage and other complications. All patients recovered, and subsequently discharged. CONCLUSIONS: In summary, anatomical right hemicolectomy was a safe and feasible method for the treatment of progressive right hemicolon carcinoma; it was worth popularizing widely.

STAT3 activation mediates epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells.

BACKGROUND/AIMS: Epithelial-to-mesenchymal transition (EMT) is critical for the development of the invasion and metastasis in human cancers. Recently, signal transducer and activator of transcription 3 (STAT3) activation has been linked to EMT program in breast cancer. However, the actual association of STAT3 activation with EMT, and its mediated tumor invasion and metastasis remains elusive in hepatocellular carcinoma (HCC). The aim of this study was to investigate the correlation between STAT3 activation and EMT, as well as the underlying mechanism involved in HCC progression. METHODOLOGY: We treated SMMC-7721 cells with a known STAT3 activator, epithelial growth factor (EGF); in the absence or presence of JSI-124, a selective STAT3 inhibitor. The EMT-associated morphologic and molecular changes of cells were analyzed. The EMT-mediated HCC cell invasion, migration and adhesion were evaluated. RESULTS: In this study, we found that STAT3 activation induced by EGF was associated significantly with morphologic changes, cytoskeleton rearrangement and molecular changes consistent with EMT in SMMC-7721 cells; STAT3 activation-mediated EMT may be transcriptionally induced by Twist. STAT3 activation-mediated EMT also promoted HCC cell invasion, migration and adhesion significantly. CONCLUSIONS: In summary, our study show for the first time that STAT3 activation may induce invasion and metastasis through the mediation of EMT in HCC cells. Activated STAT3 and EMT markers can serve as molecular targets for HCC treatment.

The Research of No-Touch Isolation Technique on the Prevention of Postoperative Recurrence and Metastasis of Hepatocellular Carcinoma after Hepatectomy.

BACKGROUND/AIMS: To evaluate the efficacy of a surgical no-touch isolation technique in primary hepatocellular carcinoma patients compared with traditional hepatectomy. METHODOLOGY: Eighty hepatocellular carcinoma patients were randomly divided into traditional hepatectomy (n = 40) and no-touch isolation technique groups (n = 40). We compared peripheral blood variations in alpha-fetoprotein mRNA, miRNA-221, miRNA-224, and miRNA-122 expression levels in both groups pre- and postoperatively using real-time fluorescent quantitative polymerase chain reaction. RESULTS: The patients in the no-touch isolation technique group had better clinical curative effect. In the traditional hepatectomy group, variations in alpha-fetoprotein mRNA copy number pre- and postoperatively indirectly indicated a significant increase in the number of exfoliated carcinoma cells induced by manipulating the liver, increasing the risk of postoperative recurrence and metastasis (P < 0.05). Traditional hepatectomy patients showed higher increases in miRNA-221 and miRNA-224 expression than those in the no-touch isolation technique group (P < 0.05). Tumor resection resulted in preoperative expression and high postoperative expression of miRNA-122. No-touch isolation technique patients showed a slight and significant increase (P < 0.01) in miRNA-122, which was positively correlated with postoperative liver function index. Conclusion: The no-touch isolation technique is more effective than traditional hepa- tectomy in tumor resection for primary hepatocellular carcinoma.

Diagnostic and prognostic significance of peroxiredoxin 1 expression in human hepatocellular carcinoma.

Peroxiredoxin 1 (Prdx1) is a member of the peroxiredoxin family of antioxidant enzymes and implicated in cell differentiation, proliferation, and apoptosis. The aim of the present study was to determine the expression and diagnostic and prognostic significance of Prdx1 in human hepatocellular carcinoma (HCC). Prdx1 expression was examined in 76 HCC patients and 20 healthy volunteers. The relationships between Prdx1 expression and clinicopathological features were analyzed. Receiver operating characteristics analysis was used to calculate the diagnostic accuracy of serum Prdx1, serum alpha-fetoprotein (AFP), and their combination. The prognostic impact of Prdx1 on overall survival (OS) and disease-free survival (DFS) of HCC patients was investigated. Prdx1-positive rate was significantly (p < 0.05) higher in HCC (77.1 %) than in adjacent non-tumorous liver tissues (18.4 %). Prdx1 immunoreactivity was positively correlated with tumor vascular endothelial growth factor expression and microvessel density. Prdx1 expression was significantly associated with tumor size, microvascular invasion, Edmondson grade, tumor capsula status, serum AFP, and tumor-node-metastasis stage. The combination of serum Prdx1 and AFP had a markedly higher area under the curve than serum Prdx1 alone. Positive Prdx1 expression was associated with unfavorable OS (p = 0.004) and DFS (p = 0.001). Multivariate analysis revealed intra-tumoral Prdx1 staining as an independent poor prognostic marker for OS (p = 0.006) and DFS (p = 0.002). Taken together, our data suggest that increased Prdx1 expression is associated with tumor angiogenesis and progression in HCC and serves as a promising biomarker for detection and prognosis of this malignancy.