Cuproptosis-related genes score and its hub gene GCSH: A novel predictor for cholangiocarcinomas prognosis based on RNA seq and experimental analyses.

Background: Recent researches have demonstrated that cuproptosis, a copper-dependent cell death mechanism, is related to tumorigenesis, progression, clinical prognosis, tumor microenvironment, and drug sensitivity. Nevertheless, the function and impact of cuproptosis in cholangiocarcinoma (CCA), remain elusive. Methods: Utilizing data obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA-CHOL) datasets, we conducted subgroup typing of CCA according to cuproptosis-related genes (CRGs) and explored functional differences and prognostic value between groups. A CRG score was established considering clinical prognosis and gene expression. Furthermore, differences in the immune microenvironment, response to immunotherapy, metabolic patterns, and cancer progression characteristics between high- and low-risk groups were examined on the basis of these scores. In vitro experiments validated the function of the key gene glycine cleavage system protein H (GCSH) in cellular and tissues, respectively. Results: Prognostic models established on the basis of subgroup genetic differences achieved satisfactory results in validation. Metabolic-related gene expression levels and tumor microenvironment distribution were significantly different between the high and low CRG groups. GCSH was revealed as the singular prognostic CRG in CCA (HR =6.04; 95% CI: 1.15-31.80). Moreover, inhibition of the cupcoptosis key gene GCSH attenuated the malignant ability of CCA cell lines in vitro, including cell proliferation, migration and invasion, and this function of GCSH may be achieved via JAK-STAT signaling in CCA. Conclusion: The CRG scoring system accurately predicts prognosis and opens up new possibilities for cuproptosis-related therapy for CCA. The cuproptosis key gene GCSH has been preliminarily confirmed as a reliable therapeutic target or prognostic marker for CCA patients.

The Role of Caspase-11 and Pyroptosis in the Regulation of Inflammation in Peri-Implantitis.

Peri-implantitis is an important cause of oral implant failure. In the past, TLR4 and TLR2 in the Toll-like family were generally considered as the key immune recognition receptors regulating peri-implantitis. However, under the guidance of this theory, there are still some unexplainable peri-implantitis symptoms. With the discovery of novel intracellular LPS receptor Caspase-11, a new understanding of inflammatory signaling and immune regulation in the development of peri-implantitis has been gained. However, the regulatory role of Caspase-11 in peri-implantitis and its crosstalk with the TLR4 pathway remain unclear. The therapeutic effect of drugs targeting Caspase-11 on peri-implantitis is still in its early stages. In view of this situation, this paper reviews the possible role of Caspase-11 in peri-implant inflammation, elaborated the entry process of LPS and the activation mechanism of Caspase-11, and analyzes the differences in Caspase-11 between commonly studied animals, mice and humans. The current research hotspots and challenges are also analyzed to provide new insights and ideas for researchers.

Low MARCO Expression is Associated with Poor Survival in Patients with Hepatocellular Carcinoma Following Liver Transplantation.

Background: Macrophage receptor with collagenous structure (MARCO) reportedly plays a crucial role in the occurrence and development of several cancers. However, the association between MARCO and the prognosis of hepatocellular carcinoma (HCC) post-liver transplantation remains poorly elucidated. Methods: We examined MARCO expression at mRNA and protein level in 145 HCC samples and adjacent nontumor tissues using quantitative reverse transcription PCR, Western blot and immunohistochemistry. Furthermore, we analyzed the correlation of MARCO expression with clinicopathologic features and prognosis. Results: We assessed the association between MARCO expression and clinicopathologic features and used the Cox proportional hazards regression model to explore the association between MARCO expression and clinical prognosis of patients with HCC post-liver transplantation. We observed that the expression of MARCO at mRNA and protein level in adjacent nontumor tissues was higher than that in the HCC tissues. Low MARCO expression in HCC tissues was correlated with higher alpha-fetoprotein levels, higher incidence of microvascular invasion, and a higher number of patients beyond Milan criteria. Kaplan-Meier survival curves showed that patients with HCC with low MARCO expression exhibited poor overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analysis revealed that MARCO expression was an independent prognostic factor for OS (hazard ratio [HR] 2.696, 95% confidence interval [CI] 1.335-5.444, P=0.006) and DFS (HR 2.867, 95% CI 1.665-4.936, P<0.001) in patients with HCC post-liver transplantation. Based on immunofluorescence analysis, MARCO expression was primarily localized to macrophages and might be associated with M2-like macrophage polarization during HCC. Conclusion: MARCO expression was downregulated in HCC and associated with poor prognosis of patients with HCC post-liver transplantation. Moreover, it could be a potential prognostic marker and therapeutic target in post-liver transplantation HCC.

LDH and GGT/ALT Ratio as Novel Prognostic Biomarkers in Hepatocellular Carcinoma Patients after Liver Transplantation.

BACKGROUND: Liver inflammation indices reflect its inflammatory microenvironment, which may play a role in the proliferation, invasion, and migration of carcinoma. This study is aimed at exploring the prognostic significance of serum lactate dehydrogenase (LDH) levels and gamma-glutamyl transferase (GGT)/alanine aminotransferase (ALT) ratio in hepatocellular carcinoma after liver transplant (LT). METHODS: We retrospectively analyzed data from 155 patients with a pathologically confirmed diagnosis of hepatocellular carcinoma who received LT between January 2013 and September 2017. We used receiver operating characteristics (ROC) curves to determine the optimal LDH and GGT/ALT ratio cut-off values. The Kaplan-Meier method and the logarithmic rank test were used to compare the survival curves without recurrence (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify factors associated with survival. RESULTS: Serum LDH levels were significantly associated with the Child-Pugh score (P = 0.037), largest tumor size (<50 vs. ≥50 mm) (P = 0.017), tumor count (<3 vs. ≥3) (P = 0.009), microvascular invasion (P = 0.006), and the Milan criteria (P ≤ 0.001). The serum GGT/ALT ratio was significantly correlated with alpha-fetoprotein (AFP) levels (of <400 vs. ≥400 ng/ml) (P ≤ 0.001), largest tumor size (of <50 vs. ≥50 mm) (P ≤ 0.001), the Edmondson grade (I-II vs. III-IV) (P = 0.028), microvascular invasion (P ≤ 0.001), and the Milan (P = 0.002) and Hangzhou criteria (P = 0.018). The survival curves showed that the patients with high LDH and the GGT/ALT ratio were associated with poor RFS and OS (P < 0.05). Univariate and multivariate analyses showed that AFP levels of ≥400 ng/ml, largest tumor size of ≥50 mm, microvascular invasion, LDH levels of ≥213.5 U/l, and the GGT/ALT ratio of ≥3.1338 were factors independently associated with RFS. CONCLUSION: Elevated LDH levels and the GGT/ALT ratio before LT were associated with poor OS and RFS in the present study. These factors could be used in the prognostication of patients with hepatocellular carcinoma undergoing LT.

Cell nucleus as endogenous biological micropump.

Micropumps can generate directional microflows in blood vessels or bio-capillaries for targeted transport of nanoparticles and cells in vivo, which is highly significant for biomedical applications from active drug delivery to precision clinical therapy. Meanwhile, they have been extensively used in the biosensing fields with their unique features of autonomous motion, easy surface functionalization, dynamic capture and effective isolation of analytes in complex biological media. However, synthetic devices for actuating microflows, including pumps and motors, generally exhibit poor or limited biocompatibility with living organisms as a result of the invasive implantation of exogenous materials into blood vessels. Here we demonstrate a method of constructing endogenous micropumps by extracting nuclei from red blood cells, thus making them intrinsically and completely biocompatible. The nuclei are extracted and then driven by a scanning optical tweezing system. By a precise actuation of the microflows, nanoparticles and cells are navigated to target destinations, and the transport velocity and direction is controlled by the multifunctional dynamics of the micropumps. With the targeted transport of functionalized micro/nanoparticles followed by a dynamic mixing in microliter blood samples, the micropumps provide considerable promises to enhance the target binding efficiency and improve the sensitivity and speed of biological assays in vivo. Furthermore, multiplexing by simultaneously driving an array of multiple nuclei is demonstrated, thus confirming that the micropumps could provide a bio-friendly high-throughput in vivo platform for the treatment of blood diseases, microenvironment monitoring, and biomedical analysis.

Correction: JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

[This corrects the article DOI: 10.18632/oncotarget.3713.].

The First Case of Ischemia-Free Kidney Transplantation in Humans.

Background: Ischemia-reperfusion injury (IRI) has been considered an inevitable event in organ transplantation since the first successful kidney transplant was performed in 1954. To avoid IRI, we have established a novel procedure called ischemia-free organ transplantation. Here, we describe the first case of ischemia-free kidney transplantation (IFKT). Materials and Methods: The kidney graft was donated by a 19-year-old brain-dead donor. The recipient was a 47-year-old man with end-stage diabetic nephropathy. The graft was procured, preserved, and implanted without cessation of blood supply using normothermic machine perfusion. Results: The graft appearance, perfusion flow, and urine production suggested that the kidney was functioning well-during the whole procedure. The creatinine dropped rapidly to normal range within 3 days post-transplantation. The levels of serum renal injury markers were low post-transplantation. No rejection or vascular or infectious complications occurred. The patient had an uneventful recovery. Conclusion: This paper marks the first case of IFKT in humans. This innovation may offer a unique solution to optimizing transplant outcomes in kidney transplantation.

Outcome of the use of paediatric donor livers in adult recipients: A single Chinese centre experience.

BACKGROUND: Paediatric liver allografts sometimes are allocated to adult recipients when there are no suitable paediatric recipients on the waiting list. However, debate exits regarding the reported outcomes of liver transplants using such small grafts. METHODS: Records from adult patients undergoing liver transplantation between February 2010 and January 2016 who received whole grafts from paediatric (≤ 13 years) donors or ideal deceased adult (18-35 years) donors were reviewed. Patient and graft survival, post-transplant liver function, and complications between the two groups were compared. RESULTS: The baseline characteristics were comparable, except that the paediatric donor allografts had smaller size. The 3-month, 1-year, and 3-year rates of patient survival were 91.3%, 85.2%, and 85.2% in the paediatric donor group and 93.4%, 88.9%, and 85.0% in the adult donor group (P = 0.947), respectively. One patient receiving a paediatric allograft developed small-for-size liver syndrome post-transplantation. There was no difference in primary non-function, early allograft dysfunction, biliary complications, vascular complications, or infection between the two groups. CONCLUSION: Our study indicates that using paediatric donor livers in well-selected adult recipients is a safe procedure, considering there was no suitable paediatric recipient. However, the risk of portal hyperperfusion should be considered in clinical cases such as size-mismatched transplants.

Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor usually resistant to chemotherapy. MicroRNAs play important roles in modulation of carcinogenesis and chemoresistance, which miR-16 has been reported to mediate chemoresistance in many types of cancers. However, the role of miR-16 in HCC remains unknown. The aim of this study was to investigate whether miR-16 is participated in chemoresistance in HCC and shed light on the underlying molecular mechanisms. The findings of the current study discover that miR-16 is down-regulated in HCC tissue and cell lines. The results demonstrate that the inhibition of miR-16 renders resistance to paclitaxel in vitro and in vivo by targeting IKBKB via NF-κB signaling pathway, suggesting that miR-16 may be a meaningful therapeutic potential to overcome drug resistance in HCC.

Does Ischemia Free Liver Procurement Under Normothermic Perfusion Benefit the Outcome of Liver Transplantation?

BACKGROUND In contrast to conventional static cold preservation, normothermic machine perfusion (NMP) provides a beneficial alternative preservation of donor livers. However, the liver still suffered cold ischemic injury before attaching to the perfusion device. MATERIAL AND METHODS To prevent cold ischemic injury during procurement, we describe a novel procedure called ischemia-free liver procurement (IFLP) under NMP. Two liver grafts were procured from brain death donor under NMP and underwent 2-hour ex vivo NMP followed by 3 and 6 hours of static cold preservation. From procurement to post-transplantation course, evidence was collected to prove that IFLP is safe and benefits recipients. RESULTS The post-transplantation course was uneventful, and the liver function tests and histological study revealed minimal hepatocyte and biliary epithelium injury during the preservation. CONCLUSIONS This preliminary experience demonstrates the clinical feasibility and safety of IFLP under NMP which offering opportunities to increase the number of donor livers and to improve the organ function.

Up-Regulation of HMGB1 Exacerbates Renal Ischemia-Reperfusion Injury by Stimulating Inflammatory and Immune Responses through the TLR4 Signaling Pathway in Mice.

BACKGROUND/AIMS: The aim of this study was to elucidate how high-mobility group box 1 (HMGB1) exacerbates renal ischemic-reperfusion injury (IRI) by inflammatory and immune responses through the toll-like receptor 4 (TLR4) signaling pathway. METHODS: A total of 30 wild-type (WT) mice and 30 TLR4 knockout (TLR4-/-) mice were selected and then randomly assigned to the Sham, I/R or HMGB1 groups. The serum and kidney tissues of all mice were collected 24 h after the perfusion. The fully automatic biochemical detector and ELISA were applied to determine the blood urea nitrogen (BUN) and serum creatinine (Scr) levels, and TNF-α, IL-1ß, IL-6, IFN-γ and IL-10 levels, respectively. HE staining was used to evaluate kidney tissue damage, immunofluorescence and immunohistochemical staining were performed to observe CD68 and MPO cell infiltration, and flow cytometry was applied to detect immune cells. qRT-PCR and Western blotting were used to detect the expressions of TLR signaling pathway-related genes and proteins, respectively. RESULTS: Compared with the Sham group, the levels of BUN, Scr, TNF-α, IL-1ß, IL-6, IFN-γ and IL-10, kidney tissue damage score, CD68 and MPO cell infiltration, the numbers of immune cells, and the expressions of TLR signaling pathway-related genes and proteins in the I/R and HMGB1 groups were significantly up-regulated. In the I/R and HMGB1 groups, the levels of BUN and Scr, TNF-α, IL-1ß, IL-6 and IFN-γ, kidney tissue damage score, CD68 and MPO cell infiltration, immune cell numbers, and TLR signaling pathway-related gene and protein expressions in the WT mice were all higher than those in the TLR4-/- mice, but IL-10 level was significantly lower. Similarly, all aforementioned indexes but IL-10 level in the WT and TLR4-/- mice were higher in the HMGB1 group than in the I/R group. CONCLUSION: Our study indicated that the up-regulation of HMGB1 could exacerbate renal IRI by stimulating inflammatory and immune responses through the TLR4 signaling pathway.c.

Upregulation of long non-coding RNA HOXA-AS2 promotes proliferation and induces epithelial-mesenchymal transition in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is the most common malignancy of the bile duct and patients with GBC have extremely poor prognoses. Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, including cell growth, differentiation, apoptosis, and cancer progression. However, the function of lncRNAs in the progression of GBC remains largely unknown. Here, we reported that HOXA cluster antisense RNA2 (HOXA-AS2) was upregulated in GBC. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited GBC cells proliferation by causing G1 arrest and promoting apoptosis, whereas HOXA-AS2 overexpression promoted cell growth. Further functional assays indicated that HOXA-AS2 overexpression significantly promoted GBC cell migration and invasion by promoting EMT. Taken together, our study demonstrates that HOXA-AS2 could act as a functional oncogene in GBC, as well as a potential therapeutic target to inhibit GBC metastasis.

A simplified multivisceral transplantation procedure for patients with combined end-stage liver disease and type 2 diabetes mellitus.

In liver transplant patients with type 2 diabetes mellitus (DM), the disease worsens after transplantation because of longterm use of diabetogenic immunosuppressive drugs, making management of those patients a great challenge. The objective of our study was to evaluate the safety and efficacy of a simplified multivisceral transplantation (SMT) procedure for the treatment of patients with end-stage liver disease and concurrent type 2 DM. Forty-four patients who had pretransplant type 2 DM were included. A total of 23 patients received SMT, and 21 patients received orthotopic liver transplantation (OLT). Patient and graft survivals, complications, diabetic control, and quality of life (QOL) were retrospectively analyzed in both groups. The 1-, 3-, and 5-year cumulative patient and graft survival rates were 91.5%, 75.4%, and 75.4% in the SMT group and were 94.4%, 64.4%, and 64.4% in the OLT group, respectively (P = 0.70). Interestingly, 95.7% (22/23) of patients achieved complete remission from DM after SMT compared with 16.7% (3/18) of patients after OLT. The occurrence of biliary complication was significantly higher in the OLT group than that in the SMT group (23.8% versus 0.0%; P = 0.01). Moreover, better QOL was observed in the SMT group than that in the OLT group. In conclusion, the SMT procedure we described here is a safe and viable option for patients with end-stage live disease and concurrent type 2 DM. This SMT procedure offers excellent transplant outcomes and QOL. Liver Transplantation 23 1161-1170 2017 AASLD.

SSRP1 Contributes to the Malignancy of Hepatocellular Carcinoma and Is Negatively Regulated by miR-497.

The aim of this study is to clarify the clinical implication and functional role of structure specific recognition protein 1 (SSRP1) in hepatocellular carcinoma (HCC) and explore the underlying mechanism of aberrant high expression of SSRP1 in cancers. In the present investigation, we validated that SSRP1 was upregulated in HCC samples. We also demonstrated that its upregulation was associated with several clinicopathologic features such as higher serum AFP level, larger tumor size, and higher T stage of HCC patients; and its high expression indicated shorter overall survival and faster recurrence. To investigate the role of SSRP1 in HCC progression, both loss- and gain-function models were established. We demonstrated that SSPR1 modulated both proliferation and metastasis of HCC cells in vitro and vivo. Furthermore, we demonstrated that SSRP1-modulated apoptosis process and its knockdown increased the sensitivity of HCC cells to doxorubicin, 5-Fluorouracil, and cisplatin. We also identified microRNA-497 (miR-497) as a posttranscriptional regulator of SSRP1. Ectopic expression of miR-497 inhibited 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SSRP1 expression at both messenger RNA and protein levels. For the first time, we proved that SSRP1 upregulation contributed to HCC development and the tumor-suppressive miR-497 served as its negative regulator.

Histone deacetylase inhibitors reduce WB-F344 oval cell viability and migration capability by suppressing AKT/mTOR signaling in vitro.

Histone deacetylase (HDAC) can blockDNA replication and transcription and altered HDAC expression was associated with tumorigenesis. This study investigated the effects of HDAC inhibitors on hepatic oval cells and aimed to delineate the underlying molecular events. Hepatic oval cells were treated with two different HDAC inhibitors, suberoylanilidehydroxamic acid (SAHA) and trichostatin-A (TSA). Cells were subjected to cell morphology, cell viability, cell cycle, and wound healing assays. The expression of proteins related to both apoptosis and the cell cycle, and proteins of the AKT/mammalian target of rapamycin (mTOR) signaling pathway were analyzed by Western blot. The data showed that HDAC inhibitors reduced oval cell viability and migration capability, and arrested oval cells at the G0/G1 and S phases of the cell cycle, in a dose- and time-dependent manner. HDAC inhibitors altered cell morphology and reduced oval cell viability, and downregulated the expression of PCNA, cyclinD1, c-Myc and Bmi1 proteins, while also suppressing AKT/mTOR and its downstream target activity. In conclusion, this study demonstrates that HDAC inhibitors affect oval cells by suppressing AKT/mTOR signaling.

Variants and haplotypes in Flap endonuclease 1 and risk of gallbladder cancer and gallstones: a population-based study in China.

The role of FEN1 genetic variants on gallstone and gallbladder cancer susceptibility is unknown. FEN1 SNPs were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method in blood samples from 341 gallbladder cancer patients and 339 healthy controls. The distribution of FEN1-69G > A genotypes among controls (AA, 20.6%; GA, 47.2% and GG 32.2%) was significantly different from that among gallbladder cancer cases (AA, 11.1%; GA, 48.1% and GG, 40.8%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-69G > A GA (OR = 1.73, 95% CI = 1.01-2.63) and the FEN1-69G > A GG (OR = 2.29, 95% CI = 1.31-3.9). The distribution of FEN1 -4150T genotypes among controls (TT, 21.8%;GT, 49.3% and GG 28.9%) was significantly different from that among gallbladder cancer cases (TT, 12.9%; GT, 48.4% and GG 38.7%), significantly increased association with gallbladder cancer was observed for subjects with both the FEN1-4150T GT(OR = 1.93, 95% CI = 1.04-2.91) and the FEN1-4150T GG(OR = 2.56, 95% CI = 1.37-5.39). A significant trend towards increased association with gallbladder cancer was observed with potentially higher-risk FEN1-69G > A genotypes (P < 0.001, χ2 trend test) and FEN14150G > T (P < 0.001, χ2 trend test) in gallstone presence but not in gallstone absence (P = 0.81, P = 0.89, respectively). In conclusion, this study revealed firstly that FEN1 polymorphisms and haplotypes are associated with gallbladder cancer risk.

Histone Deacetylase Inhibitors Inhibit the Proliferation of Gallbladder Carcinoma Cells by Suppressing AKT/mTOR Signaling.

Gallbladder carcinoma is an aggressive malignancy with high mortality mainly due to the limited potential for curative resection and its resistance to chemotherapeutic agents. Here, we show that the histone deacetylase inhibitors (HDACIs) trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA) reduce the proliferation and induce apoptosis of gallbladder carcinoma cells by suppressing the AKT/mammalian target of rapamycin (mTOR) signaling. Gallbladder carcinoma SGC-996 cells were treated with different concentrations of TSA and SAHA for different lengths of time. Cell proliferation and morphology were assessed with MTT assay and microscopy, respectively. Cell cycle distribution and cell apoptosis were analyzed with flow cytometry. Western blotting was used to detect the proteins related to apoptosis, cell cycle, and the AKT/mTOR signaling pathway. Our data showed that TSA and SAHA reduced SGC-996 cell viability and arrested cell cycle at the G1 phase in a dose- and time-dependent manner. TSA and SAHA promoted apoptosis of SGC-996 cells, down-regulated the expression of cyclin D1, c-Myc and Bmi1, and decreased the phosphorylation of AKT, mTOR p70S6K1, S6 and 4E-BP1. Additionally, the mTOR inhibitor rapamycin further reduced the cell viability of TSA- and SAHA-treated SGC-996 cells and the phosphorylation of mTOR, whereas the mTOR activator 1,2-dioctanoyl-sn-glycero-3-phosphate (C8-PA) exerted the opposite influence. Our results demonstrate that histone deacetylase inhibitors (HDACIs) suppress the proliferation of gallbladder carcinoma cell via inhibition of AKT/mTOR signaling. These findings offer a mechanistic rationale for the application of HDACIs in gallbladder carcinoma treatment.

Interaction between microRNA-181a and TNFAIP1 regulates pancreatic cancer proliferation and migration.

We investigated the role of microRNA 181a (miR-181a) and its downstream target tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) in pancreatic cancer regulation. Quantitative real-time PCR (qRT-PCR) was applied to evaluate the gene expression of miR-181a in seven pancreatic cancer cell lines. MiR-181a inhibitor lentivirus (miR-181a-IN) was used to down-regulate miR-181a in Capan-1 and AsPC-1 cells. The effects of miR-181a down-regulation on pancreatic cancer were evaluated by in vitro proliferation assay and migration assay. Targeting of miR-181a on TNFAIP1 in pancreatic cancer was evaluated by dual-luciferase reporter assay and western blot. TNFAIP1 was either upregulated by pcDNA3.1 (+) expression vector or down-regulated by siRNA in Capan-1 and AsPC-1 cells. The subsequent effects of TNFAIP1 upregulation or down-regulation on miR-181a mediated pancreatic cancer regulation were also evaluated through in vitro proliferation and migration assays. The in vivo effect of miR-181a down-regulation on pancreatic tumor growth was evaluated by a xenograft assay. MiR-181a was consistently upregulated in pancreatic cancer cell lines. MiR-181a down-regulation inhibited proliferation and migration in vitro, and upregulated TNFAIP1 in pancreatic cancer cells. Ectopic TNFAIP1 overexpression had similar tumor-suppressive effects on pancreatic cancer proliferation and migration as miR-181a down-regulation, whereas siRNA-mediated TNFAIP1 down-regulation had opposite or oncogenic effects on pancreatic cancer. In vivo pancreatic xenograft showed miR-181a recapitulated the in vitro anti-tumor effects and its regulation on TNFAIP1. MiR-181a played a critical role in regulating pancreatic cancer growth and migration, likely interacting with TNFAIP1.

JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells.

JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.

Estrogen receptorß2 regulates interlukin-12 receptorß2 expression via p38 mitogen-activated protein kinase signaling and inhibits non-small-cell lung cancer proliferation and invasion.

Lung cancer is one of the most common types of cancer and is the leading cause of cancer-related mortality worldwide. Estrogens are known to be involved in the development and progression of non-small-cell lung cancer (NSCLC). These effects are initially mediated through binding of estrogen to estrogen receptors (ERs), in particular ERß2. Our preliminary studies demonstrated that ERß2 and interleukin-12 receptorß2 (IL-12Rß2) expression are correlated in NSCLC. The present study investigated the expression of these proteins in NSCLC cells and how changes in their expression affected cell proliferation and invasion. In addition, it aimed to explore whether p38 mitogen-activated protein kinase (p38MAPK) is involved in the regulation of IL-12Rß2 expression by ERß2. An immunocytochemical array was used to observe the distribution of ERß2 and IL-12Rß2. Co-immuoprecipitation was employed to observe the interaction between p38MAPK and IL-12Rß2, by varying the expression of ERß2 and p38MAPK. Western-blot analysis and reverse transcription-polymerase chain reaction assays were used to investigate the mechanism underlying ERß2 regulation of IL-12Rß2 expression. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, scratch wound healing and Transwell assays were used to investigate the impact of ERß2 on proliferative, invasive and migratory abilities of NSCLC cells. ERß2 was predominantly found in the cytoplasm and nucleus, whilst IL-12Rß2 was largely confined to the cytoplasm, although a degree of expression was observed in the nucleus. Compared with normal bronchial epithelial cells, IL-12Rß2 and ERß2 were overexpressed in the NSCLC cell groups. Coimmuoprecipitation demonstrated an interaction between p38MAPK and IL-12Rß2. ERß2 appeared to upregulate IL-12Rß2 expression and inhibition of p38MAPK attenuated this effect. ERß2 and IL-12Rß2 expression inhibited the proliferation, metastasis and invasion of NSCLC cell lines, but knockout of IL-12Rß2, even in the presence of ERß2, led to an increase in NSCLC cell proliferation and invasiveness. In conclusion, to the best of our knowledge this study is the first to demonstrate that IL-12Rß2 may be important in the mechanisms underlying ERß2 inhibition of NSCLC development, and that this interaction may be mediated via p38MAPK.