Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, ...we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.
Adult left lobe (LL) living donor liver transplantation (LDLT) has not generally been recognized as a feasible procedure because of the problem of graft size. The objectives of this study were to ...assess the feasibility and short‐ and long‐term results of adult LL LDLT in comparison with right lobe (RL) LDLT. Data on 200 consecutive LL LDLTs, including five retransplants, were retrospectively compared with those of 112 RL LDLTs, in terms of survival, complications and donor morbidity. The mean graft weight to standard volume ratio of LL grafts was 38.7% whereas that of RL grafts was 47.6% (p < 0.0001). The 1‐, 5‐ and 10‐year patient survival rates of LL LDLT were 85.6%, 77.9% and 69.5%, respectively, which were comparable to those of RL LDLT (89.8%, 71.3% and 70.7%, respectively). The incidence of small‐for‐size syndrome was higher in LL LDLT (19.5%) than in RL LDLT (7.1%) (p < 0.01). The overall donor morbidity rates were comparable between LL (36.0%) and RL (34.8%), whereas postoperative liver function tests and hospital stay were significantly better (p < 0.0001) in LL donors. In conclusion, adult LL LDLT has comparable outcomes to that of RL LDLT. LL LDLT is viable and is the first choice in adult LDLT.
A series of 200 adult left lobe living donor liver transplants demonstrates the feasibility of this procedure with comparable outcome to that of right lobe living donor liver transplantation.
The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth.
We retrospectively investigated the impact of angiotensin I-converting ...enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs).
Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis.
The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.
Operative mortality for a right lobe (RL) donor in adult living donor liver transplantation (LDLT) is estimated to be as high as 0.5–1%. To minimize the risk to the donor, left lobe (LL)‐LDLT might ...be an ideal option in adult LDLT. The aim of the study was to assess the feasibility of LL‐LDLT between adults based on a single‐center experience of 107 LL‐LDLTs performed over 8 years. The mean graft weight of LL grafts was 452 g, which amounted to 40.5% of the estimated standard liver volume of the recipients. The overall 1‐, 3‐ and 5‐year patient survival rates in LL‐LDLT were 81.4, 76.9 and 74.7%, respectively, which were comparable to those of RL‐LDLT. Twenty‐six grafts (24.3%) were lost for various reasons with three losses directly attributable to small‐for‐size graft syndrome. Post‐operative liver function and hospital stay in LL donors were significantly better and shorter than that in RL donors, while the incidence of donor morbidity was comparable between LL and RL donors. In conclusion, LL‐LDLT was found to be a feasible option in adult‐to‐adult LDLT. Further utilization of LL grafts should be undertaken to keep the chance of donor morbidity and mortality minimal.
Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small ...remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS‐398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS‐398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS‐398 treatment. In the 90% PH model, administration of NS‐398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver.
The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, alleviating the lobular derangement and improves the prognosis for animals bearing a small remnant liver.
Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling ...activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/β-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/β-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.
Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for ...HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.
Abstract Introduction Accurate pretransplant estimation of the recipient's standard liver volume (SLV) is important. The purpose of this study was to compare reported formulas for clinical estimation ...of liver volume among Japanese adults. Methods We reviewed data on 70 healthy adults (46 men, 24 women, ages 20 to 65 years old) evaluated for living donor liver transplantation. Liver volume (LV) was measured using two- or three-dimensional computed tomography volumetry (CTV). The formulas of DeLand (LV = 1020 × body surface area BSA − 220), Urata (LV = 706.2 × BSA + 2.4), Noda (LV = 50.12 × BW0.78 ), Heinemann (LV = 1072.8 × BSA − 345.7), Vauthey (LV = 18.51 × BW + 191.8) and Yoshizumi (LV = 772 × BSA) were applied to estimate LV. We calculated the differences for individual donors betwen CTV and LV estimated by each formula. Results Mean LVs as estimated by the formulae of DeLand and Heinemann et al were significantly greater ( P < .01) than the mean CTV, while LV estimated by the formula of Urata was significantly less ( P < .05) than the CTV. The formulas of DeLand and Heinemann overestimated LV, while the formula of Urata underestimated it. The formulae of Noda et al and Yoshizumi et al tended to underestimate the LV when the CTV was greater than 1600 cm3 . When the Yoshizumi formula was applied, the number of donors with an acceptable difference (±15%) between CTV and estimated LV was 55 (78.6%). Conclusions The Yoshizumi formula was applicable, especially for patients with a BSA < 2.0, whereas the well-known Urata formula made LV underestimates.
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