Upregulation of HSD11B1 promotes cortisol production and inhibits NK cell activation in pancreatic adenocarcinoma.

Cortisol is a glucocorticoid hormone that has immunosuppressive function. Elevated basal cortisol levels are present in patients with some kinds of cancers, but its role in the microenvironment of pancreatic adenocarcinoma (PAAD) remains unclear. This study analyzed the expression of genes involved in cortisol generation by using high-throughput sequencing data from TCGA portal and found HSD11B1 was significantly upregulated in patients with PAAD. The correlations between HSD11B1 level and the expression of 23 immunosuppressive receptors were analyzed by Spearman's correlation analysis. The function of HSD11B1 was examined in primary NK cells and PAAD cell lines. The levels of cortisol in medium and cell lysates were detected by ELISA. In vitro killing assay was used to evaluate the cytotoxicity of NK cells. Cell surface levels of CD96, Tim-3, PD-1, TIGIT, CTLA-4, NKp46, NKp30, NKD2G and LFA-1A, and intracellular levels of CD107a and IFN-γ were examined by flow cytometry. We observed that patients with higher HSD11B1 level had shorter survival time. HSD11B1 is positively correlated with the mRNA levels of 11 immunosuppressive receptors in PAAD. Higher HSD11B1 level relates to reduced abundance of activated NK cells in the tumors. HSD11B1 overexpressed NK cells exhibit exhausted phenotype with increased cortisol production, reduced viability, and reduced cytotoxicity against cancer cells. Overexpression of HSD11B1 did not change the viability of tumor cells but upregulated cortisol production. Targeting HSD11B1 by a specific inhibitor improved the NK cells responsiveness. In conclusion, HSD11B1 is upregulated in patients with PAAD, and higher HSD11B1 level is related to poor prognosis. Upregulation of HSD11B1 in NK and tumor cells increased the production and secretion of cortisol and induces NK cell exhaustion.

Strategies and Recent Advances on Improving Efficient Antitumor of Lenvatinib Based on Nanoparticle Delivery System.

Lenvatinib (LVN) is a potentially effective multiple-targeted receptor tyrosine kinase inhibitor approved for treating hepatocellular carcinoma, metastatic renal cell carcinoma and thyroid cancer. Nonetheless, poor pharmacokinetic properties including poor water solubility and rapid metabolic, complex tumor microenvironment, and drug resistance have impeded its satisfactory therapeutic efficacy. This article comprehensively reviews the uses of nanotechnology in LVN to improve antitumor effects. With the characteristic of high modifiability and loading capacity of the nano-drug delivery system, an active targeting approach, controllable drug release, and biomimetic strategies have been devised to deliver LVN to target tumors in sequence, compensating for the lack of passive targeting. The existing applications and advances of LVN in improving therapeutic efficacy include improving longer-term efficiency, achieving higher efficiency, combination therapy, tracking and diagnosing application and reducing toxicity. Therefore, using multiple strategies combined with photothermal, photodynamic, and immunoregulatory therapies potentially overcomes multi-drug resistance, regulates unfavorable tumor microenvironment, and yields higher synergistic antitumor effects. In brief, the nano-LVN delivery system has brought light to the war against cancer while at the same time improving the antitumor effect. More intelligent and multifunctional nanoparticles should be investigated and further converted into clinical applications in the future.

Progress and application of lung-on-a-chip for lung cancer.

Lung cancer is a malignant tumour with the highest incidence and mortality worldwide. Clinically effective therapy strategies are underutilized owing to the lack of efficient models for evaluating drug response. One of the main reasons for failure of anticancer drug therapy is development of drug resistance. Anticancer drugs face severe challenges such as poor biodistribution, restricted solubility, inadequate absorption, and drug accumulation. In recent years, "organ-on-a-chip" platforms, which can directly regulate the microenvironment of biomechanics, biochemistry and pathophysiology, have been developed rapidly and have shown great potential in clinical drug research. Lung-on-a-chip (LOC) is a new 3D model of bionic lungs with physiological functions created by micromachining technology on microfluidic chips. This approach may be able to partially replace animal and 2D cell culture models. To overcome drug resistance, LOC realizes personalized prediction of drug response by simulating the lung-related microenvironment in vitro, significantly enhancing therapeutic effectiveness, bioavailability, and pharmacokinetics while minimizing side effects. In this review, we present an overview of recent advances in the preparation of LOC and contrast it with earlier in vitro models. Finally, we describe recent advances in LOC. The combination of this technology with nanomedicine will provide an accurate and reliable treatment for preclinical evaluation.

Lenvatinib resistance mechanism and potential ways to conquer.

Lenvatinib (LVN) has been appoved to treat advanced renal cell carcinoma, differentiated thyroid carcinoma, hepatocellular carcinoma. Further other cancer types also have been tried in pre-clinic and clinic without approvation by FDA. The extensive use of lenvastinib in clinical practice is sufficient to illustrate its important therapeutic role. Although the drug resistance has not arised largely in clinical, the studies focusing on the resistance of LVN increasingly. In order to keep up with the latest progress of resistance caused by LVN, we summerized the latest studies from identify published reports. In this review, we found the latest report about resistance caused by lenvatinib, which were contained the hotspot mechanism such as the epithelial-mesenchymal transition, ferroptosis, RNA modification and so on. The potential ways to conquer the resistance of LVN were embraced by nanotechnology, CRISPR technology and traditional combined strategy. The latest literature review of LVN caused resistance would bring some ways for further study of LVN. We call for more attention to the pharmacological parameters of LVN in clinic, which was rarely and would supply key elements for drug itself in human beings and help to find the resistance target or idea for further study.

Overexpression of rhophilin 2 promotes pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the seventh leading cause of global cancer deaths. In recent years, targeted therapy has been used for pancreatic cancer; however, the drugs available for use in targeted therapy for pancreatic cancer are still very limited. Hence, identification of novel targeted molecules for PDAC is required. Rhophilin 2 (RHPN2) was proven to be a driver gene in glioblastoma. However, the function of RHPN2 in PDAC remains unknown. In the present study, the function of RHPN2 was investigated. The RHPN2 levels were overexpressed by pcDNA3.1-RHPN2 and downregulated by si-RHPN2. Cell proliferation was assessed using the MTT assay and apoptosis was assessed using flow cytometry. The results revealed that high RHPN2 levels in PDAC tissue were correlated with a low overall survival rate of patients with PDAC. Inhibition of RHPN2 reduced SW1990 and PANC1 proliferation and increased the rate of apoptosis. Network analysis demonstrated that centrosomal protein 78 expression was negatively correlated with RHPN2 expression. In conclusion, the present study demonstrated that RHPN2 may promote PDAC making it a potential candidate for targeted therapy.

Overexpression of Rhophilin Rho GTPase-binding protein 2 promotes hepatocellular carcinoma.

Hepatocellular carcinoma is a serious public health problem in China. The mortality rate associated with the majority of cancer types has decreased as a result of targeted therapy. However, the mortality rates associated with hepatocellular carcinoma have not improved; therefore, the identification of new molecular targets is required for the development of novel targeted therapies. In the present study, a new molecular target, Rhophilin Rho GTPase-binding protein 2 (RHPN2), was identified. The levels of RHPN2 protein in tumor tissues were assessed via immunohistochemistry, while the mRNA levels were analyzed via reverse transcription-quantitative PCR. Additionally, cell viability was tested via MTT analysis. RHPN2 expression was upregulated in hepatocellular carcinoma tissues compared with that of matched adjacent normal tissues. More importantly, low expression of RHPN2 in patients with hepatocellular carcinoma was associated with an improved prognosis rate compared with patients with high expression. Downregulation of RHPN2 reduced the proliferation of hepatocellular carcinoma cells and increased the rate of apoptosis, whereas overexpression of RHPN2 demonstrated the opposite effects. Hepatocyte nuclear factor 1α was implicated in the mechanism of RHPN2. Overall, these data indicated that overexpression of RHPN2 may promote hepatocellular carcinoma.

Long non-coding RNA CASC2 upregulates PTEN to suppress pancreatic carcinoma cell metastasis by downregulating miR-21.

BACKGROUND: The mechanism of pancreatic cancer metastasis remains poorly understood. Recently, lncRNA CASC2 has been demonstrated to be a tumor suppressor in various types of cancer. This study aimed to explore the mechanism of CASC2 in the regulation of pancreatic cancer metastasis. METHODS: The expression levels of CASC2 and miR-21 in pancreatic cells were detected by qRT-PCR. Using specific expression vectors, including mimics or shRNA, the expression levels of CASC2, miR-21 and PTEN in pancreatic cells were altered. The association between CASC2, miR-21 and PTEN was detected. Then, cell migration and invasion were assessed using the transwell assay. RESULTS: CASC2 expression was downregulated in the pancreatic cancer cell lines CAPAN-1, BxPC-3, JF305, PANC-1 and SW1990 compared with levels in normal human pancreatic HPDE6-C7 cells. CACS2 overexpression inhibited the migration and invasion of PANC-1 cells and significantly inhibited the expression of miR-21 and PTEN. MiR-21 was a direct target of CACS2. The overexpression of miR-21 significantly abolished the antimetastatic effects of CASC2 on PANC-1 cells. Moreover, the downregulation of PTEN significantly abolished the antimetastatic effects of CASC2. CONCLUSION: CASC2 functions as a tumor suppressor in pancreatic cancer cells to inhibit tumor cell migration and invasion. Our work revealed a novel regulatory mechanism of the CASC2/miR-21/PTEN axis that may be important in pancreatic cancer.

MiR-132 promotes the proliferation, invasion and migration of human pancreatic carcinoma by inhibition of the tumor suppressor gene PTEN.

MicroRNA (miRNAs) emerges as key oncogene or tumor suppressor in a variety of cancers including pancreatic carcinoma. In this study, we detected the role of miR-132 in development and progression of pancreatic cancer and the underlying mechanism. First, the expression of miR-132 in pancreatic carcinoma and adjacent non-cancerous tissues were detected by qRT-PCR. Then, the role of miR-132 in biological function of pancreatic carcinoma cells was investigated. Our results identified that miR-132 was generally upregulated in pancreatic carcinoma, and phosphatase and tensin homolog (PTEN) was generally downregulated. miR-132 and PTEN were associated with advanced tumor size, lymph node metastasis and Tumor-Nodes-Metastases (TNM) stage of pancreatic carcinoma. Downregulation of miR-132 inhibited proliferation, migration and invasion of pancreatic carcinoma cells. In contrast, overexpression of miR-132 promoted proliferation, migration and invasion of pancreatic carcinoma cells. The luciferase reporter system demonstrated PTEN is a direct target of miR-132. Overexpression of PTEN abrogated the induction of miR-132 on proliferation, migration and invasion of pancreatic carcinoma cells. Taken together, miR-132 promotes the proliferation, invasion and migration of human pancreatic cancer by inhibition of PTEN, and could be a tumor oncogene in development and progression of pancreatic carcinoma, and might be a candidate prognostic biomarker and a promising target for new treatment of human pancreatic cancer.

Fibrosis-4 Model Influences Results of Patients with Hepatocellular Carcinoma Undergoing Hepatectomy.

BACKGROUND: Several noninvasive models based on routine laboratory index have been developed to predict liver fibrosis. Our aim is to discuss whether these indexes could predict prognosis in patients with hepatocellular carcinoma undergoing hepatectomy. METHODS: This study retrospectively enrolled 788 consecutive hepatocellular carcinoma patients undergoing liver resection in the cohort. Univariate and multivariate analysis were used to identify the risk factors of complications, survival, and disease-free survival. RESULTS: Fibrosis-4 index had the best prediction ability for cirrhosis among other noninvasive models. Both the univariate and multivariate analyses showed that fibrosis-4 was independent risk factor for survival and disease-free survival. With the optimal cutoff value of 3.15, patients with fibrosis-4 ⩾3.15 had higher postoperative hepatic insufficiency (P=0.006) and worse survival than the fibrosis-4<3.15 group. The corresponding 1-year, 3-year, and 5-year overall survival were 80.9%, 56.3%, and 44.6% in the High fibrosis-4 group and were 86.5%, 69.9%, and 63.2% in the Low fibrosis-4 group, respectively (P<0.001). Worse disease-free survival was also observed in the fibrosis-4 ⩾3.15 group; the corresponding 1-year, 3-year, and 5-year disease-free survival were 74.9%, 45.3%, and 24.6% for the fibrosis-4 ⩾3.15 group and were 81.8%, 54.9%, and 34.4% for the fibrosis-4<3.15 group (P=0.009). CONCLUSIONS: Fibrosis-4 is useful for assessing the short-term and long-term results for hepatocellular carcinoma patients with liver resection.

Terlipressin in the treatment of hepatorenal syndrome: A systematic review and meta-analysis.

BACKGROUND: Hepatorenal syndrome is a fatal complication of advanced cirrhosis. Terlipressin is the most widely used treatment method, however, the therapy effects remain inconsonant. We aim to systematically assess the safety and efficacy of terlipressin for hepatorenal syndrome. METHODS: We conducted a systematic review and meta-analysis. Randomized controlled trials involving terlipressin for hepatorenal syndrome were included in a systematic literature search. Two authors independently assessed the studies for inclusion and extracted the data. A meta-analysis was conducted to estimate the safety and efficacy of terlipressin for hepatorenal syndrome. RESULTS: A total of 18 randomized controlled trials including 1011 patients were included. Hepatorenal syndrome reverse rate was 42.0% in the terlipressin group and 26.2% in the non-terlipressin group. Terlipressin had greater hepatorenal syndrome reverse rate and renal function improvement rate than placebo and octreotide in the management of HRS. Comparing to norepinephrine, terlipressin had similar efficacy, but with more adverse events. No significant difference of the efficacy was found between terlipressin and dopamine treatment. The subgroup analysis for type 1 HRS had the above same results, except that the adverse events were not significant different between norepinephrine group and terlipressin group. CONCLUSIONS: Terlipressin was superior to placebo and octreotide for reversal of hepatorenal syndrome and improving renal function, but it had no superiority comparing to norepinephrine.

Immediate postoperative Fibrosis-4 predicts postoperative liver failure for patients with hepatocellular carcinoma undergoing curative surgery.

BACKGROUND: Postoperative liver failure remains the main complication and predominant cause of hepatectomy-related mortality for patients undergoing liver resection. AIM: Our aim is to investigate whether immediate postoperative Fibrosis-4 could predict postoperative liver failure. METHODS: We retrospectively enrolled 1353 consecutive hepatocellular carcinoma patients undergoing radical resection. The characteristics and clinical outcomes were compared between patients with high and low immediate postoperative Fibrosis-4. Risk factors for hepatic failure were evaluated by univariate and multivariate analysis. RESULTS: Using a receiver operating characteristic curve, immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure (AUROC=0.647, P<0.001). With the optimal cut-off value of 5.9, the high postoperative Fibrosis-4 group (Fibrosis-4<5.9) had higher postoperative complication (39.1% vs 28.6%, P<0.001), mortality (2.8% vs 0.6%, P<0.001) and liver failure (13.9% vs 6.2%, P<0.001). In addition, patients with high Fibrosis-4 had worse and delayed recovery of liver function. By univariate and multivariate analysis, Fibrosis-4, as well as liver removed volume, total bilirubin and albumin was identified as independent risk factor for postoperative liver failure. CONCLUSIONS: Immediate postoperative Fibrosis-4 showed good prediction ability for postoperative liver failure, and required measure should be taken to prevent liver failure when high postoperative Fibrosis-4 appeared.

New Evidence and Perspectives on the Management of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus.

Portal vein tumor thrombosis (PVTT) is an intractable condition but common phenomenon in hepatocellular carcinoma (HCC). HCC patients with PVTT may have worse liver function, a higher chance of comorbidity related to portal hypertension, lower tolerance to treatment and poorer prognoses. In Western guidelines, patients are offered palliative treatment with sorafenib or other systemic agents because HCC with PVTT is grouped together with metastatic HCC during the planning of its management. In recent years, various treatment options have become available for patients with HCC and PVTT. Therapy has also shifted toward evidence-based treatment. However, policies for the management of HCC with PVTT have not been established. This comprehensive literature review aims to present current and available management options for patients with HCC and PVTT. Evidence is mainly based on studies published after 2010.

Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma patients after curative resection, a systematic review and meta-analysis.

BACKGROUND: Cytokine-induced killer cells have been used as an adjuvant treatment for hepatocellular carcinoma with curative treatment. However, the outcomes remain controversial. AIM: We conducted this meta-analysis to assess the safety and efficacy of cytokine-induced killer cells. METHODS: Randomized controlled trials on cytokine-induced killer cells for hepatocellular carcinoma after curative treatments were identified by electronic searches. A meta-analysis was carried out to examine disease-free survival, overall survival rate and adverse effect. RESULTS: Six randomized controlled trials with 844 patients (85.9% with hepatitis B or C) were included. Our meta-analysis showed that cytokine-induced killer cells can not only improve the 1-year (RR=1.23, P<0.001), 2-year (RR=1.37, P<0.001) and 3-year (RR=1.35, P=0.004) disease-free survival, but also improve the 1-year (RR=1.08, P=0.001), 2-year (RR=1.14, P<0.001) and 3-year (RR=1.15, P=0.02) overall survival. However, it failed to affect the 4-year and 5-year disease-free survival and overall survival (P>0.05). At the same time, cytokine-induced killer cells treatment was proved to be a safe strategy with the comparable adverse events comparing to the control group (P=0.39). CONCLUSIONS: This review provides the best available evidence that adjuvant cytokine-induced killer cells treatment can be safely used to improve the early disease-free survival and survival of hepatitis B or C related hepatocellular carcinoma.

The tumor suppressor role of miR-4782-3p in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortalities in China. Although advances have been made in treatments, the prognosis of HCC patients has not improved significantly. MicroRNAs (miRNA) play important roles in all stage of the progress of HCC. miR-4782-3p takes part in the pathogenesis of non-small cell lung cancer (NSCLC). However, the role of miR-4782-3p in HCC remains unknown. In the present study, we found that miR-4782-3p had low expression in HCC tissues. The low expression of miR-4782-3p indicated shorter survival of HCC patients. Moreover, the low expression of miR-4782-3p promoted HCC cells growth and inhibited cell apoptosis. We confirmed that USP14 was targeted by miR-4782-3p in HCC cells.