Jinglin Xia

Caveolin-1 Confers Resistance of Hepatoma Cells to Anoikis by Activating IGF-1 Pathway.

Background/Aims: Anoikis resistance is a prerequisite for hepatocellular carcinoma (HCC) metastasis. The role of Caveolin-1 (CAV1) in anoikis resistance of HCC remains unclear. Methods: The oncogenic effect of CAV1 on anchor-independent growth and anoikis resistance was investigated by overexpression and knockdown of CAV1 in hepatoma cells. IGF-1 pathway and its downstream signals were detected by immunoblot analysis. Caveolae invagination and IGF-1R internalization was studied by electron microscopy and 125I-IGF1 internalization assay, respectively. The role of IGF-1R and tyrosine-14 residue (Y-14) of CAV1 was explored by deletion experiment and mutation experiment, respectively. The correlation of CAV1 and IGF-1R was further examined by immunochemical analysis in 120 HCC specimens. Results: CAV1 could promote anchor-independent growth and anoikis resistance in hepatoma cells. CAV1-overexpression increased the expression of IGF-1R and subsequently activated PI3K/Akt and RAF/MEK/ERK pathway, while CAV1 knockdown showed the opposite effect. The mechanism study revealed that CAV1 facilitated caveolae invagination and 125I-IGF1 internalization. IGF-1R deletion or Y-14 mutation reversed CAV1 mediated anchor-independent growth and anoikis resistance. In addition, CAV1 expression was positively related to IGF-1R expression in human HCC tissues. Conclusion: CAV1 confers resistance of hepatoma cells to anoikis by activating IGF-1 pathway, providing a potential therapeutic target for HCC metastasis.

The development of precision medicine in clinical practice

Precision medicine allows a dramatic expansion of biological data, while there is still an urgent need to understand and insight the exact meaning of those data to human health and disease. This has led to an increasing wealth of data unanalyzed. The concept of precision medicine is about the customization of healthcare, with decisions and practices tailored to an individual patient based on their intrinsic biology in addition to clinical “signs and symptoms”. Construction of a standardized model for the integration of data from various platforms is the central mission of the ‘New Disease Management Model’. The model is helpful for the development of new taxonomy of diseases and subtypes, to personalize therapy based on patient genetic profiles. A rapid progression of precision therapy has been made recently. Clinical trials have shown the therapeutic efficacy of discovered and developed therapeutic agents has improved. However, next-generation drugs would be designed for disease subtypes with more specificity, efficacy and lower toxicity.

The international effort: building the bridge for Translational Medicine: Report of the 1st International Conference of Translational Medicine (ICTM)

BackgroundSupported by the International Society for Translational Medicine (ISTM), Wenzhou Medical College and the First Affiliated Hospital of Wenzhou Medical College, the International Conference on Translational Medicine (ICTM) was held on October 22–23, 2011 in Wenzhou, China. Nearly 800 registrants attended the meeting, primarily representing institutes and hospitals in Europe, The United States of America, And Asia, and China. The meeting was chaired and organized by Dr. Xiangdong Wang, Xiaoming Chen, Richard Coico, Jeffrey M. Drazen, Richard Horton, Francesco M. Marincola, Laurentiu M. Popescu, Jia Qu and Aamir Shahzad.FindingsThe meeting focused on the communication of the need to foster translational medicine (TM) by building and broadening bridges between basic research and clinical studies at the international level. The meeting included distinguished TM experts from academia, the pharmaceutical and diagnostics industries, government agencies, regulators, and clinicians and provided the opportunity to identify shared interests and efforts for collaborative approaches utilizing cutting edge technologies, innovative approaches and novel therapeutic interventions. The meeting defined the concept of TM in its two-way operational scheme and emphasized the need for bed to bench efforts based directly on clinical observation.ConclusionsIt was the meeting participants’ realization that the shared main goals of TM include breaking the separation between clinic practice and basic research, establishing positive feedback by understanding the basis of expected and unexpected clinical outcomes and accelerating basic research relevant to human suffering. The primary objectives of the meeting were two-fold: to accelerate the two-way translation by informing the participants representing the different disciplines about the state of art activities around TM approaches; and to identify areas that need to be supported by redirecting limited resources as well as identifying new sources of funding. This report summarizes key concepts presented during the meeting representing the state-of-art translational research and salient aspects of the ensuing discussions.

The potential of CXCL5 as a target for liver cancer – what do we know so far?

CXCL5, epithelial cell derived neutrophil attractant 78, is a CXC chemokine predominantly expressed on epithelial cells. It has specificity for CXCR2 receptors and is involved in the recruitment and activation of neutrophils. CXCL5 is considered a therapeutic target in liver cancer, since treatment with small-interfering RNAs or antibodies against CXCL5 can suppress tumor growth, proliferation, migration and invasion. Experimental evidence demonstrated that CXCL5 antibodies could reduce the tumor growth and synergistically increase the efficiency of the tyrosine kinase inhibitor, Gefitinib, without the addition of toxicity. A number of challenges are encountered and should be considered during the development and clinical application of CXCL5 target-specific drugs. The specificity of CXCL5 as a therapeutic target for certain types and duration of cancer should be more carefully clarified, since it seems that CXCL5 is involved in many molecular pathways and crosstalk between targeted chemokines/receptors. The concept that CXCL5 serves as the therapeutic target for liver cancer was evidenced by preclinical studies, and is the beginning of CXCL5-based drug discovery and development.

Pathogenesis of chronic pancreatitis: A comprehensive update and a look into the future.

Chronic pancreatitis is a relatively frequent condition usually caused by alcoholic abuse but also due to recurrent gallstone disease, metabolic endocrine disorders and haemochromatosis, among others. Specific types such as hereditary and autoimmune pancreatitis should be particularly kept in mind and emphasized, as they require specific treatment and attention. The possibility to identify gene mutations has also increased and this is likely to decrease the overall total number of “idiopathic” chronic pancreatitis cases. Pancreatic stellate cells have been identified as potential key players in the progression of chronic pancreatitis and the development of fibrogenesis, which are activated either during repeated attacks of necro-inflammation or directly by toxic factors. The inhibition or modulation of pancreatic stellate cells could represent a way of potential intervention in patients with chronic pancreatitis in the future.

Actinidia chinensis Planch root extract inhibits cholesterol metabolism in hepatocellular carcinoma through upregulation of PCSK9

Actinidia chinensis Planch root extract (acRoots) is a traditional Chinese medicine with anti-tumor efficacy. To investigate the mechanisms responsible for this activity, we examined the effects of acRoots on cholesterol metabolism in hepatocellular carcinoma (HCC). mRNA chip analysis was used to identify the metabolic genes regulated by acRoots. The effects of acRoots on cholesterol synthesis and uptake were evaluated by measuring intracellular cholesterol levels and 3,3′-dioctadecylindocarbocyanine-labeled low-density lipoprotein (Dil-LDL) uptake. Expression of metabolic genes was analyzed using quantitative reverse transcription PCR, western blotting, and flow cytometry. acRoots reduced the viability of LM3 and HepG2 cells at 5 mg/mL and HL-7702 cells at 30 mg/mL. Gene expression profiling revealed that treatment with acRoots altered expression of genes involved in immune responses, inflammation, proliferation, cell cycle control, and metabolism. We also confirmed that acRoots enhances expression of PCSK9, which is important for cholesterol metabolism. This resulted in decreased LDL receptor expression, inhibition of LDL uptake by LM3 cells, decreased total intracellular cholesterol, and reduced proliferation. These effects were promoted by PCSK9 overexpression and rescued by PCSK9 knockdown. Our data demonstrate that acRoots is a novel anti-tumor agent that inhibits cholesterol metabolism though a PCSK9-mediated signaling pathway.

FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. Methods: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. Results: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. Conclusions: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression.

Lymphocytes in Liver Cancer

Tumor infiltrating lymphocytes (TIL) are an important part of tumor surveillance systems and a representative component of antitumor immune responses. The liver, as an immunological organ, is specially equipped with liver-associated lymphocytes. Liver cancer can be regarded as an unresolved lesion of chronic inflammation and its microenvironment can control tumor progression via TIL activation and proliferation, predominantly CD8(+) and CD4(+) T lymphocytes and natural killer cells. However, increased CD4(+) CD25(+) Foxp3(+) T-regulatory lymphocytes (Tregs) may impair the effector function of CD8(+) T cells, thus promote liver cancer progression and invasion. Moreover, the intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival, which indicates combination of the depletion of Tregs and the concomitant stimulation of effector T cells may be an effective immunotherapy strategy for liver cancer. As an emerging discipline, translational bioinformatics specially focus on genomics, proteomics, metabolomics, and bioinformatics. It can increase our understanding in the molecular mechanisms of systems immunology. This chapter aims to overview the biological and functional characters of different lymphocytes in liver cancer, describe lymphocyte-related cytokines, chemokines, mediators, lymphocyte-related bioinformatics and network in order to define liver cancer specific biomarkers as well as therapeutic targets.

Liver ischaemia following vascular occlusion: A century's experience.

Although a century has passed since Dr. Hogarth Pringle described vascular inflow occlusion in order to arrest liver haemorrhage (following trauma), the Pringle manoeuvre is still in use. In the present paper we discuss liver ischaemia and reperfusion injury and the potential ways to prevent or diminish their effects. Pringle’s manoeuvre and vascular occlusion of the liver In 1908 James Hogarth Pringle, originally an Australian but from 1896 until his retirement in 1923 spending his surgical career at Glasgow Royal Infirmary, published a paper in the Annals of Surgery on the arrest of hepatic haemorrhage caused by trauma. Pringle covered a broad surgical spectrum and also wrote scientific papers ranging from circulation to the diagnosis of skull fractures, and was particularly recognized for his works on fractures and melanomas. His paper in the Annals of Surgery describes the use of inflow occlusion of the hepatic pedicle, thus including both the hepatic artery and the portal vein, in the management of liver trauma. Regrettably, all eight of his patients died, but even so an effect on the liver bleeding was noted and the procedure has since then been known as the Pringle manoeuvre, and is still widely practised 100 years later. The article is also of interest, not only because of the introduction of a vascular inflow occlusion to the liver, but also because Dr. Pringle challenged the risks described following obstruction of the hepatic and portal vessels as proposed by Langenbuch, with early death (in experimental animals) due to stagnation of blood in the portal area. In the ‘‘translational’’ research performed by Hogarth Pringle, after initial experiences in patients, the Pringle manoeuvre was studied in rabbits and found to have no notable side effects, but provided apparent control of liver bleeding. Dr. Pringle’s four rabbits recovered from the operation, and thus the gain by achieving control of the liver bleeding seems to outweigh the potential side effects of controlled liver ischaemia. The paper in the Annals of Surgery also discusses two other items that in more modern times are used in clinical practice. The first is the packing of liver injuries, which is now part of the initial damage control. Secondly, Dr. Pringle proposed non-operative management of minor liver ruptures as the haemorrhage could spontaneously be arrested, in which process the increased pressure within the abdomen could