HHLA2 promotes hepatoma cell proliferation, migration, and invasion via SPP1/PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2, or B7-H5) in HCC remains unclear. Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels. HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OE enhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway. Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy and safety of ultrasound-guided percutaneous microwave ablation (MWA) for hepatocellular carcinoma (HCC) adjacent to large vessels with those far from large vessels. METHODS: The clinical data of patients who underwent ultrasound-guided percutaneous MWA for HCC were retrospectively analyzed between January 2011 and December 2018 in Shengjing Hospital. Patients with HCC adjacent to large vessels were included in the Vessel group, the remaining patients were included in the Control group. Propensity score matching analysis was used to reduce confounding bias. The rates of complete ablation, local recurrence, recurrence-free survival (RFS), overall survival (OS) and complications were compared between the two groups. RESULTS: A total of 134 patients with 157 nodules (size range, 0.6-3.8 cm) were enrolled in this study, 23 in the Vessel group and 111 in the Control group. A total of 21 patients in the Vessel group (91.3%) and 105 patients in the Control group (94.6%) achieved complete ablation (p = .902). Following 1:2 propensity score matching, 22 patients were included in the Vessel group and 40 patients were enrolled in the Control group. Local recurrence was observed in 2 (9.1%) patients in the Vessel group and 5 (12.5%) in the Control group (p = .86). No significant difference in local recurrence rate, RFS and OS were observed between the two groups. CONCLUSIONS: Ultrasound-guided percutaneous MWA appears to be a safe procedure and can achieve comparable oncological efficacy for HCC abutting large vessels.

Changes of Endocan and its effect on hepatic stem cells during the rapid proliferation process of residual liver after ALPPS procedure.

To establish a stable animal model of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), as well as to explore whether Endocan and HGF/c-Met signalling pathway participate in the regeneration of residual liver through hepatic stem cells after ALPPS procedure. C57BL/6J male mice weighing 18-22 g were used in this study. The liver regeneration index was expressed as the ratio of Future Liver Remnant (FLR)/Body weight (BW) × 100%. Expression of hepatic stem cell marker CK19 was assessed by immunohistochemical method. Serum levels of vascular endothelial growth factor (VEGF) and Endocan were detected by ELISA. VEGF, Endocan and c-Met contents in residual liver were observed by Western blot analysis. The expression levels of Endocan and HGF/c-Met pathway-related genes were evaluated by qRT-PCR. Compared with the portal vein ligation (PVL) group and sham group, the ALPPS group had more CK19 positive cells and a higher liver regeneration index (P < .05). The serum levels of VEGF in the ALPPS group were increased significantly (P < .05) from the first day and decreased from the second day after surgery, and maintained consistently higher than that of the sham group (P < .05). Western blot showed that the expressions of VEGF and Endocan in ALPPS group were significantly higher than those in both sham and PVL groups at different time points. The Endocan plays a role in the rapid regeneration of residual liver after ALPPS, likely through the interaction with the HGF/c-Met pathway to affect the hepatic stem cell population. SIGNIFICANCE OF THE STUDY: Our animal study provides valuable insights on the effect of Endocan in the process of rapid regeneration of residual liver after ALPPS, which would lead to the possible expansion of clinical research on ALPPS surgery and further studies on its molecular underpinning during liver regeneration.

GNAS promotes inflammation-related hepatocellular carcinoma progression by promoting STAT3 activation.

BACKGROUND: Hepatocellular carcinoma (HCC) is still the most common cause of cancer-related mortality worldwide and accumulating studies report that HCC is frequently linked to chronic inflammation. G-protein alpha-subunit (GNAS)-activating mutations have recently been reported to form a rare subgroup of inflammatory liver tumors. In this study, we investigated the roles of GNAS in inflammation-related HCC progression and its underlying mechanism. METHODS: Lipopolysaccharides (LPS) and diethylnitrosamine were employed to stimulate HCC cells to an induced inflammatory response. qRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of GNAS in HCC tissues and cell lines. Expression levels of proinflammatory cytokines were detected by qRT-PCR and ELISA. N6-methyladenosine (m6A) methylation of GNAS mRNA was detected by RNA-binding protein immunoprecipitation (RIP). Transcription factors activation profiling plate array was performed to investigate the underlying mechanism in GNAS promoting interleukin-6 (IL-6) expression in HCC cells. HCC cell invasion was determined by transwell assay in vitro, and tumorigenesis was assessed with a subcutaneous xenograft mouse model of HCC. RESULTS: We found that LPS stimulation promotes GNAS expression in HCC cells through increasing m6A methylation of GNAS mRNA. The high expression level of GNAS promotes LPS-induced HCC cell growth and invasion by interacting with signal transducer and activator of transcription 3 (STAT3). Furthermore, GNAS knockdown inhibits LPS induced-IL-6 expression in HCC cells by suppressing STAT3 activation. Moreover, we found that GNAS promotes LPS-induced STAT3 activation in HCC cells through inhibiting long non-coding RNA TPTEP1 interacting with STAT3. In addition, GNAS expression promotes HCC development in mice and is related to poor survival. CONCLUSIONS: Our findings for the first time indicate a tumor-promoting role of GNAS in inflammation-related HCC progression and provide a novel potential target for HCC therapy.

Efficacy and factors affecting the choice of enucleation and liver resection for giant hemangioma: a retrospective propensity score-matched study.

BACKGROUND: Liver resection (LR) and enucleation (EN) are the main surgical treatment for giant hepatic hemangioma (HH), but how to choose the type of surgery is still controversial. This study aimed to explore the efficacy and the factors affecting the choice of open procedure for HH. METHODS: The data for patients with pathologically confirmed HH who underwent open surgery from April 2014 to August 2020 were analyzed retrospectively. Univariate and multivariate analyses with logistic regression were performed to disclose the factors associated with the choice of EN or LR. Propensity score matching (PSM) analysis was used to compare the efficacy of the two procedures. RESULTS: A total of 163 and 110 patients were enrolled in the EN and LR groups. Following 1:1 matching by PSM analysis, 66 patients were selected from each group. Centrally located lesions (OR: 0.131, 95% CI 0.070-0.244), tumors size > 12.1 cm (OR: 0.226, 95% CI 0.116-0.439) and multiple tumors (OR: 1.860, 95% CI 1.003-3.449) were independent factors affecting the choice of EN. There was no significant difference in the median operation time (156 vs. 195 min, P = 0.156), median blood loss (200 vs. 220 ml, P = 0.423), blood transfusion rate (33.3% vs. 33.3%, P = 1.000), mean postoperative feeding (3.1 vs. 3.3 d, P = 0.460), mean postoperative hospital stay (9.5 vs. 9.0 d, P = 0.206), or the major complication rates between the two groups. CONCLUSIONS: Peripherally located lesions, tumors size ≤ 12.1 cm and multiple tumors were more inclined to receive EN. There was no significant difference in the efficacy of EN or LR.

Beneficial impact of microwave ablation-assisted laparoscopic hepatectomy in cirrhotic hepatocellular carcinoma patients: a propensity score matching analysis.

PURPOSE: In this study, we evaluated the efficacy of microwave ablation-assisted laparoscopic hepatectomy (MLH) for the management of hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: Data from HCC patients with liver cirrhosis who underwent laparoscopic hepatectomy (LH) or MLH in Shengjing Hospital (Shenyang, China) were retrospectively analyzed from January 2013 to June 2017. The demographic characteristics, clinical features, intraoperative parameters and surgical outcomes were analyzed and compared. Propensity scores matching (PSM) analysis was used to minimize bias. RESULTS: A total of 54 patients were enrolled in the MLH group and 39 patients in the LH group. Following 1:1 matching by PSM analysis, 26 patients were selected from each group. Compared to the LH group, patients in the MLH group had significantly decreased intraoperative bleeding (48.0 vs. 203.9 ml, p < .0001) and reduced demand for hepatic inflow occlusion (0 vs. 6, p = .009). No significant difference was observed in average operation time (155.7 vs. 148.5 min) and postoperative hospitalization time (8.3 vs. 9.3 d) between the MLH and LH groups. Similarly, the 1-year and 3-year recurrence-free survival (RFS) rates as well as the 1-year and 3-year overall survival (OS) rates of the MLH and LH groups were not significantly different (83.1 vs. 82.4% and 64.6 vs. 36.6% as well as 100 vs. 95.8% and 93.8 vs. 59.1%, respectively: p > .05). CONCLUSIONS: MLH significantly decreased intraoperative bleeding and reduced the need for hepatic occlusion without compromising the surgical outcome. Therefore, microwave ablation could be a valuable tool for LH in HCC patients with cirrhosis.

Autophagy Contributes to Liver Regeneration After Portal Vein Ligation in Rats.

BACKGROUND This study investigated the effect of 70% portal vein ligation (PVL), a widely used procedure for inducing rapid liver regeneration, on the expression of autophagy-related proteins in non-ligated liver lobes in rats. MATERIAL AND METHODS Rats were subjected to either sham (n=30, major portal vein branches were exposed but kept intact) or PVL (n=30, major portal vein branches were double-ligated) operations. Liver samples were collected 12, 24, 48, 72, and 168 h after the operation. Liver volume, liver color, non-ligated liver percentage, and the expressions of light chain (LC) 3, beclin 1, and cyclin D1 in the non-ligated liver lobes were determined. RESULTS When compared to sham rats, increased (P<0.001) growth of the non-ligated liver lobes was observed in PVL rats as early as 12 h after surgery; an increased (P≤0.001) LC3 II/I ratio was observed in the non-ligated lobes of PVL rats as early as 24 h after surgery. Increased expressions of beclin 1 (P≤0.001) and cyclin D1 (P<0.001) were observed in the non-ligated lobes of PVL rats from 12 to 72 h after surgery and from 12 to 168 h after surgery, respectively, when compared to sham rats. In the non-ligated lobes, the expressions of beclin 1 and cyclin D1 were linearly and positively correlated with the LC3 II/I ratio. CONCLUSIONS Autophagy is activated in the non-ligated liver after PVL. Both beclin 1 and cyclin D1 are linearly and positively correlated with autophagy activity in the PVL-induced rapid liver regeneration model.

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.

Lipopolysaccharide stimulates endogenous ß-glucuronidase via PKC/NF-κB/c-myc signaling cascade: a possible factor in hepatolithiasis formation.

Hepatolithiasis is commonly encountered in Southeastern and Eastern Asian countries, but the pathogenesis mechanism of stone formation is still not well understood. Now, the role of endogenous ß-glucuronidase in pigment stones formation is being gradually recognized. In this study, the mechanism of increased expression and secretion of endogenous ß-glucuronidase during hepatolithiasis formation was investigated. We assessed the endogenous ß-glucuronidase, c-myc, p-p65, and p-PKC expression in liver specimens with hepatolithiasis by immunohistochemical staining, and found that compared with that in normal liver samples, the expression of endogenous ß-glucuronidase, c-myc, p-p65, and p-PKC in liver specimens with hepatolithiasis significantly increased, and their expressions were positively correlated with each other. Lipopolysaccharide (LPS) induced increased expression of endogenous ß-glucuronidase and c-myc in hepatocytes and intrahepatic biliary epithelial cells in a dose- and time-dependent manner, and endogenous ß-glucuronidase secretion increased, correspondingly. C-myc siRNA transfection effectively inhibited the LPS-induced expression of endogenous ß-glucuronidase. Furthermore, NF-κB inhibitor pyrrolidine dithiocarbamate or PKC inhibitor chelerythrine could effectively inhibit the LPS-induced expression of c-myc and endogenous ß-glucuronidase, and the expression of p-p65 was also partly inhibited by chelerythrine. Our clinical observations and experimental data indicate that LPS could induce the increased expression and secretion of endogenous ß-glucuronidase via a signaling cascade of PKC/NF-κB/c-myc in hepatocytes and intrahepatic biliary epithelial cells, and endogenous ß-glucuronidase might play a possible role in the formation of hepatolithiasis.

Armc8 regulates the invasive ability of hepatocellular carcinoma through E-cadherin/catenin complex.

Armc8 (armadillo-repeat-containing protein 8) was proved to promote disruption of E-cadherin complex through regulating α-catenin degradation. In this study, we investigated Armc8 expression in hepatocellular carcinoma using immunohistochemistry (IHC). The positive rate of Armc8 expression in hepatocellular carcinoma was 53.9 % and higher than that in normal hepatic tissues (9.2 %) (p < 0.05). Clinicopathological analysis shows that Armc8 expression in hepatocellular carcinoma was significantly associated with larger tumor size (≥5 cm), multiple tumor numbers, higher pathological grade (media and poor), advanced TNM stages (II/III), and advanced BCLC stages (B/C). Western blot study also detected higher Armc8 expression in hepatocellular carcinoma cells including HepG2, HCC97L, and SMMC-7721 than in human hepatic cell Bel-7402. We further use specific small interfering RNAs (siRNAs) to knock down Armc8 expression in HepG2 cells and found that knockdown of Armc8 expression significantly inhibited the invasive ability of HepG2 cells. Downregulation of Armc8 expression significantly upregulated α-catenin, ß-catenin, and E-cadherin expression in HepG2 cells. Immunofluorescent study shows that knockdown of Armc8 expression restored E-cadherin expression in membrane of HepG2 cells. These results indicate that Armc8 may be a potential cancer marker in hepatocellular carcinoma and may regulate cancer invasion through E-cadherin/catenin complex.

High serum microRNA-122 level is independently associated with higher overall survival rate in hepatocellular carcinoma patients.

Previous studies have shown that some microRNAs (miRs) are intensively involved in the development of hepatocellular carcinoma. We analyzed the prognostic role of serum microRNA (miR-122) levels in hepatocellular carcinoma patients using a retrospective design. MiR-122 levels in 122 hepatocellular carcinoma patients were measured, and Cox regression analysis was performed to analyze the prognostic role of miR-122 in hepatocellular carcinoma, and the hazard ratio (HR) with 95 % confidence interval (95 %CI) was used to evaluate its prognostic role. Patients with large tumor size had lower levels of serum miR-122 (P = 0.04). However, there was no significant association of serum miR-122 levels with other clinical characteristics. Kaplan-Meier method showed that there was higher overall survival rate in hepatocellular carcinoma patients with high serum miR-122 levels compared with those with low miR-122 level (P < 0.01). When using Cox regression analysis, high serum miR-122 level was independently associated with better overall survival in hepatocellular carcinoma patients (HR = 0.26; 95 %CI 0.14-0.47, P < 0.01). Subgroup analysis by gender showed that high serum miR-122 level was independently associated with better overall survival in male patients (HR = 0.08; 95 %CI 0.03-0.22, P < 0.01), but not in female patients (HR = 0.48; 95 %CI 0.18-1.32, P = 0.16). Thus, the outcomes in the analysis suggest that high serum miR-122 level is independently associated with higher overall survival rate in hepatocellular carcinoma patients, and it is a good biomarker of better prognosis in patients with hepatocellular carcinoma.

Preconditioning with glutamine protects against ischemia/reperfusion-induced hepatic injury in rats with obstructive jaundice.

OBJECTIVE: To ascertain whether glutamine (Gln) pretreatment protects rats with obstructive jaundice from hepatic ischemia/reperfusion (I/R) injury and to determine the underlying molecular mechanisms. METHODS: An obstructive jaundice rat model was developed by bile duct ligation. On the first day after the operation, all rats were randomized into two groups and received oral Gln or normal saline (NS) daily for 7 days. Then both groups underwent a 15-min liver ischemia via the Pringle maneuver. Blood samples as well as liver and intestinal tissues were harvested and measured after 1, 6 and 24 h of reperfusion. RESULTS: The results showed that the histological morphology of the liver and intestinal tissues significantly improved in the Gln group after I/R injury compared with the NS group. Serum proteins and enzymes associated with hepatic function also significantly improved in the Gln group. The level of glutathione increased and the levels of malondialdehyde and myeloperoxidase decreased in the Gln group. The levels of interleukin-1ß and tumor necrosis factor-α decreased in the Gln group. Moreover, bcl-2 protein expression was upregulated and intercellular adhesion molecule 1 and bax protein expression downregulated in the Gln group; the caspase 3 mRNA level significantly increased in the Gln group. CONCLUSIONS: The study demonstrates that preconditioning with Gln significantly improves hepatic structure and function after I/R injury in rats with obstructive jaundice. The protective effect of Gln was mediated by the inhibition of reactive oxygen species and inflammation as well as a reduction in hepatocyte apoptosis.

Idiopathic desmoid-type fibromatosis of the pancreatic head: case report and literature review.

Desmoid-type fibromatosis (DTF) is an uncommon nonmetastatic fibrous neoplasm. Sporadic intraperitoneal DTF is rarely described in current literature. We herein report a case of DTF of unknown cause involving the pancreatic head. A 41-year-old man presented with recurrent epigastric pain and weight loss. An abdominal computed tomography scan showed a well-delineated solid cystic mass inside the pancreatic head. Pylorus-preserving pancreaticoduodenectomy was performed due to the patient's debilitating symptoms and suspected malignancy. The pathological examination revealed massive fibroblastic proliferation arising from the musculoaponeurotic tissues, consistent with a diagnosis of DTF. Immunohistochemical phenotyping determined positive immunoreactivity to vimentin and ß-catenin, but negative immunoreactivity to smooth muscle actin, CD117, CD34, or S-100, confirming the diagnosis of DTF. No local recurrence or distant metastasis was found during a 24-month follow-up. Radical resection is recommended as first-line treatment for pancreatic DTF. Long-term follow-up studies are required to establish the prognosis of pancreatic DTF.

The tumor burden score may be a discriminator in microwave ablation versus liver resection for hepatocellular carcinoma within the Milan criteria: a propensity score matching and inverse probability of treatment weighting study.

Purpose: This study aims to compare the prognostic outcome of resection (RES) and microwave ablation (MWA) in different tumor burden score (TBS) cohorts. Patients and Methods: We retrospectively analyzed 479 patients with primary hepatocellular carcinoma (HCC) who underwent RES (n = 329) or MWA (n = 150) with curative intent at our institution. We assessed their overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier curve. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to minimize selection and confounding biases. Multivariate Cox regression was used to define the association between surgical modalities and outcomes. Results: Following PSM, in the TBS ≤3 cohort, the cumulative 1-, 3-, 5- year OS in the RES and MWA groups were 92.5% vs. 98.8%, 82.7% vs. 90.0%, and 82.7% vs. 83.2% (P = 0.366), respectively. The corresponding PFS rates in the RES and MWA groups were 82.7% vs. 88.0%, 63.6% vs. 68.3% and 55.2% vs. 56.3, respectively (P = 0.218). In the TBS >3 cohort, the cumulative 1-, 3-, 5- year OS between the RES and MWA groups were 92.5% vs. 95.0%, 82.8% vs. 73.2% and 76.3% vs. 55.1%, (P = 0.034), respectively. The corresponding PFS rates in the RES and MWA groups were 78.0% vs. 67.5%, 63.6% vs. 37.5% and 55.2% vs. 37.1%, respectively (P = 0.044). The IPTW analysis showed similar results as shown in PSM analysis. The multivariate Cox regression indicated that the type of surgical modality was not associated with a poorer prognostic outcome in the TBS ≤3 cohort, unlike in the TBS >3 cohort. Conclusion: TBS, as a discriminator, might help guide treatment decision-making for HCC within the Milan criteria.

Impact of three-dimensional reconstruction visualization technology on short-term and long-term outcomes after hepatectomy in patients with hepatocellular carcinoma: a propensity-score-matched and inverse probability of treatment-weighted multicenter study.

BACKGROUND: Three-dimensional reconstruction visualization technology (3D-RVT) is an important tool in the preoperative assessment of patients undergoing liver resection. However, it is not clear whether this technique can improve short-term and long-term outcomes in patients with hepatocellular carcinoma (HCC) compared with two-dimensional (2D) imaging. METHOD: A total of 3402 patients from five centers were consecutively enrolled from January 2016 to December 2020, and grouped based on the use of 3D-RVT or 2D imaging for preoperative assessment. Baseline characteristics were balanced using propensity score matching (PSM, 1:1) and stabilized inverse probability of treatment-weighting (IPTW) to reduce potential selection bias. The perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Cox-regression analysis was used to identify the risk factors associated with RFS. RESULTS: A total of 1681 patients underwent 3D-RVT assessment before hepatectomy (3D group), while 1721 patients used 2D assessment (2D group). The PSM cohort included 892 patient pairs. In the IPTW cohort, there were 1608.3 patients in the 3D group and 1777.9 patients in the 2D group. In both cohorts, the 3D group had shorter operation times, lower morbidity and liver failure rates, as well as shorter postoperative hospital stays. The 3D group had more margins ≥10 mm and better RFS than the 2D group. The presence of tumors with a diameter ≥5 cm, intraoperative blood transfusion and multiple tumors were identified as independent risk factors for RFS, while 3D assessment and anatomical resection were independent protective factors. CONCLUSION: In this multicenter study, perioperative outcomes and RFS of HCC patients following 3D-RVT assessment were significantly different from those following 2D imaging assessment. Thus, 3D-RVT may be a feasible alternative assessment method before hepatectomy for these patients.

The role of hepatocyte nuclear factor 4alpha in metastatic tumor formation of hepatocellular carcinoma and its close relationship with the mesenchymal-epithelial transition markers.

BACKGROUND: Mesenchymal-epithelial transition (MET) is now suggested to participate in the process of metastatic tumor formation. However, in hepatocellular carcinoma (HCC) the process is still not well revealed. METHODS: Paraffin-embedded tissue samples were obtained from 13 patients with HCC in Shengjing Hospital of China Medical University. The expression of E-cadherin, Fibronectin, N-cadherin, Vimentin, Hepatocyte nuclear factor 4alpha (HNF4alpha), Snail and Slug was assessed in primary tumors and their corresponding metastases by immunohistochemical staining. Next, the expression of HNF4alpha and E-cadherin in four HCC cell lines was examined. Furthermore, SK-Hep-1 cells were transfected with human HNF4alpha expression vector, and the change of E-cadherin expression was assessed. RESULTS: 45.2% (14/31) of the lesions in the metastases showed increased E-cadherin expression compared with the primaries, suggesting the possible occurrence of MET in metastatic tumor formation of HCC, as re-expression of E-cadherin is proposed to be the important hallmark of MET. The occurrence of MET was also confirmed by the reduced expression of Fibronectin (54.8%, 17/31), N-cadherin (38.7%, 12/31) and Vimentin (61.3%, 19/31) in the metastases. 45.2% (14/31) of the lesions in the metastases also showed increased HNF4alpha expression, and 67.7% (21/31) and 48.4% (15/31) of metastases showed decreased Snail and Slug expression respectively. Statistical results showed that the expression of HNF4alpha was positively related with that of E-cadherin, and negatively correlated with that of Snail, Slug and Fibronectin, suggesting that the expression change of the MET markers in the metastatic lesions might be associated with HNF4alpha. Among the four HCC cell lines, both HNF4alpha and E-cadherin expressed high in Hep3B and Huh-7 cells, but low in SK-Hep-1 and Bel-7402 cells. Furthermore, the expression of E-cadherin increased accordingly when SK-Hep-1 cells were transfected with human HNF4alpha expression vector, further confirming the role of HNF4alpha in the regulation of E-cadherin expression. CONCLUSIONS: Our clinical observations and experimental data indicate that HNF4alpha might play a crucial role in the metastatic tumor formation of HCC, and the mechanism may be related with the process of phenotype transition.

Undifferentiated embryonal sarcoma of the liver in a middle-aged adult with systemic lupus erythematosus.

Adult primary undifferentiated embryonal sarcoma of the liver (UESL) is a rare disease. While the etiology of UESL remains largely unknown, association with systemic inflammatory disorders has been observed. Here, we report a case of UESL in a 46-year-old woman with systemic lupus erythematosus (SLE) and without chronic hepatitis or liver cirrhosis. Systematic review of the publicly available English language medical literature identified only 27 cases of UESL in patients aged >45 years and none with SLE. Our patient presented with abdominal pain and had a 2-year history of SLE. Abdominal ultrasonography and enhanced computed tomography revealed a solid mass in the right lobe of the liver. Presumptive diagnosis of atypical hepatocellular carcinoma was made and the patient was treated with segmentectomy of S5 and S4a and cholecystectomy. The final diagnosis of UESL was made according to the pathology results. Since SLE patients may be at increased risk of malignancy, it is possible that the SLE pathogenesis may have contributed to the development of UESL in our patient. According to this case, UESL should be considered when SLE patients present with hepatic space-occupying lesions.

Resection of a malignant paraganglioma located behind the retrohepatic segment of the inferior vena cava.

BACKGROUND: Resection of a retrocaval paraganglioma is technically challenging due to limited tumor accessibility and proximity to the vena cava. CASE PRESENTATION: A large, malignant paraganglioma was found behind the retrohepatic segment of the inferior vena cava of a 60-year-old male. During resection of this rare paraganglioma, the left lateral lobe of the liver, a portion of the caudate lobe of the liver, and the gallbladder were also removed. Unfortunately, the patient died six months after surgery due to hepatic metastasis. CONCLUSION: This case demonstrates that a partial hepatectomy may be necessary to improve tumor accessibility during resection of a retrocaval paraganglioma, particularly if the tumor is proximal to the vena cava. Furthermore, palliative treatments may help prevent tumor recurrence and metastasis of malignant paragangliomas.

Potential Treatment Strategies for Hepatocellular Carcinoma Cell Sensitization to Sorafenib.

Liver cancer is highly malignant, has a low sensitivity to chemotherapy, and is associated with poor patient prognosis. The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). For over 10 years, before the discovery of lenvatinib, sorafenib was only first-line therapeutic agent available for the treatment of advanced HCC. However, several clinical studies have shown that a considerable proportion liver cancer patients are insensitive to sorafenib. Very few patients actually substantially benefit from treatment with sorafenib, and the overall efficacy of the drug has not been satisfactory; therefore, sorafenib has attracted considerable research attention. This study, which is based on previous studies and reports, reviews the potential mechanisms underlying sorafenib resistance and summarizes combination therapies and potential drugs that can be used to sensitize HCC cells to sorafenib.

CgB promotes EMT and stemness via MAPK pathway in colonic neuroendocrine carcinoma.

The incidence of colorectal neuroendocrine tumors is increasing every year with poor prognosis. Members of Chromogranin family proteins have been shown to be associated with cancer metastasis; however, the role of chromogranin B in colonic neuroendocrine carcinoma (NEC) is unknown. In this study, we investigated the expression and function of CgB in colonic NEC. Using RNA-seq data from GSE 9576 and GSE 142720 datasets, we analyzed the differentially expressed genes between the normal and NEC samples, which protein levels were further validated using the Human Protein Atlas (HPA) databases. Moreover, immunohistochemistry staining and biological experiments were conducted to examine the expression and function of CgB in colonic NEC. Western blot was also performed to confirm the effect of CgB on epithelial mesenchymal transition (EMT) and its related pathways. We found that the expression level of CgB was significantly higher in colonic NEC tissues than in the adjacent tissues. The upregulation of CgB promoted cell invasion and migration as well as activated EMT and stemness. Mechanistically, both pathway enrichment analysis and Western blot analysis confirmed that CgB overexpression activated p38 MAPK and ERK pathways, while silencing CgB showed the opposite effects. Collectively, our results suggested that CgB activated p38 MAPK and ERK pathways, thereby contributing to the development of colonic NEC.