Kaixiong Tao

Tim‐3/galectin‐9 signaling pathway mediates T‐cell dysfunction and predicts poor prognosis in patients with hepatitis B virus‐associated hepatocellular carcinoma

The interaction between T cell immunoglobulin‐ and mucin‐domain‐containing molecule (Tim‐3) expressed on T helper 1 (Th1) cells, and its ligand, galectin‐9, negatively regulates Th1‐mediated immune responses. However, it is poorly understood if and how the Tim‐3/galectin‐9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim‐3/galectin‐9 pathway in patients with hepatitis B virus (HBV)‐associated HCC. We detected different levels of galectin‐9 expression on antigen‐presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin‐9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim‐3 expression was increased on CD4+ and CD8+ T cells in HCC as compared to the adjacent tissues, and Tim‐3+ T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor‐infiltrating T‐cell‐derived interferon (IFN)‐γ stimulated the expression of galectin‐9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim‐3+ T cells and galectin‐9+ KCs in HCC. Functional studies demonstrated that blockade of the Tim‐3/galectin‐9 signaling pathway importantly increased the functionality of tumor‐infiltrating Tim‐3+ T cells as shown by increased T‐cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim‐3+ tumor‐infiltrating cells were negatively associated with patient survival. Conclusion: Our work demonstrates that the Tim‐3/galectin‐9 signaling pathway mediates T‐cell senescence in HBV‐associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV‐associated HCC. (HEPATOLOGY 2012)

Morbidity and Mortality of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: A Randomized Controlled Trial

PURPOSE The safety and efficacy of radical laparoscopic distal gastrectomy (LG) with D2 lymphadenectomy for the treatment of advanced gastric cancer (AGC) remain controversial. We conducted a randomized controlled trial to compare laparoscopic and conventional open distal gastrectomy with D2 lymph node dissections for AGC. PATIENTS AND METHODS Between September 2012 and December 2014, 1,056 patients with clinical stage T2-4aN0-3M0 gastric cancer were eligible for inclusion. They were randomly assigned to either the LG with D2 lymphadenectomy group (n = 528) or the open gastrectomy (OG) with D2 lymphadenectomy group (n = 528). Fifteen experienced surgeons from 14 institutions in China participated in the study. The morbidity and mortality within 30 days after surgery between the LG (n = 519) and the OG (n = 520) groups were compared on the basis of the modified intention-to-treat principle. Postoperative complications were stratified according to the Clavien-Dindo classification. RESULTS The compliance rates of D2 lymphadenectomy were similar between the LG and OG groups (99.4% v 99.6%; P = .845). The postoperative morbidity was 15.2% in the LG group and 12.9% in OG group with no significant difference (difference, 2.3%; 95% CI, -1.9 to 6.6; P = .285). The mortality rate was 0.4% for the LG group and zero for the OG group (difference, 0.4%; 95% CI, -0.4 to 1.4; P = .249). The distribution of severity was similar between the two groups (P = .314). CONCLUSION Experienced surgeons can safely perform LG with D2 lymphadenectomy for AGC.

PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site.

Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3β inhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.

Sericin/Dextran Injectable Hydrogel as an Optically Trackable Drug Delivery System for Malignant Melanoma Treatment

Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericins photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems.

HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection

Peritoneal metastasis of colorectal cancer is a major clinical issue and results in poor prognosis for patients after surgical resection. Here, we found that abdominal surgery trauma induced high release of high-mobility group box 1 (HMGB1) in the peritoneal cavity of mice. Recombinant HMGB1 injected in the peritoneal cavity recruited abundant myeloid derived suppressor cells (MDSCs) after the surgical trauma. HMGB1 Box-A and gemcitabine reduced the recruitment of MDSCs in the peritoneal cavity after the operation and ameliorated the peritoneal metastasis burden of colon cancer in mouse model. These results showed that abdominal surgery trauma leads to a large amount of HMGB1 released in the peritoneal cavity which recruits numerous MDSCs to promote peritoneal metastasis of colon cancer after curative surgery.

miR-152 suppresses gastric cancer cell proliferation and motility by targeting CD151

We aimed to study the post-translational regulation of CD151 by the microRNA miR-152. CD151 is highly expressed in gastric cancer (GC) and has been shown to accelerate GC by enhancing invasion and metastasis; however, its regulation is still unclear. Our results showed decreased expression of miR-152 in GC tissue samples and cell lines. In addition, miR-152 complementation significantly inhibits both the proliferation and motility of GC cells. CD151 was found to be a target of miR-152, and overexpression of CD151 attenuated the suppressive effect of miR-152. Our findings highlight an essential role of miR-152 in the regulation of proliferation and motility of GC cells and suggest a potential application of miR-152 in GC treatment.

Inhibiting Enhancer of Zeste Homolog 2 Promotes Cellular Senescence in Gastric Cancer Cells SGC-7901 by Activation of p21 and p16

Cellular senescence, which can be defined as a stress response preventing the propagation of cells that have accumulated potentially oncogenic alterations, is invariably associated with a permanent cell cycle arrest. Enhancer of zeste homolog 2 (EZH2) as a member of polycomb group proteins and its targets include cell cycle regulatory proteins, which govern cell cycle progression and cellular senescence. In this study, we report that EZH2 depletion promotes the senescent state in human gastric cancer cells SGC-7901. We found that EZH2 functionally suppressed the senescent state in human gastric cancer cells SGC-7901. EZH2 depletion inhibited cell proliferation, arrested cellular cycle, restored features of a cellular senescence phenotype, and promoted doxorubicin-induced senescence. To prove that EZH2 expression contributes substantially to the change of key cell cycle regulators, we showed that p21 and p16 were activated to a certain extent upon EZH2 depletion and activation of p21 was in a p53-independent manner. Taken together, our data suggest that EZH2 depletion promotes the progression of senescence by mediating the activation of tumor suppressor genes p21 and p16, and could serve as a potential epigenetic target for gastric cancer therapy.

Maresin 1, a Proresolving Lipid Mediator, Mitigates Carbon Tetrachloride-Induced Liver Injury in Mice

Maresin 1 (MaR 1) was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb) and mitogen-activated protein kinases (MAPKs) in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway.

MicroRNA-152 regulates immune response via targeting B7-H1 in gastric carcinoma

MiR-152 has been reported may be involved in carcinogenesis in gastric cancer. However, its role has not been comprehensively investigated in gastric cancer. We found miR-152 in human gastric cancer tissues were significantly lower than that in matched adjacent normal tissues. Meanwhile, lower miR-152 was also found in gastric cancer cell lines. The stage, tumor size and lymph node metastasis rate were significant higher in low–miR-152 group in clinical patients. Furthermore, there was a marked correlation between the levels of miR-152 and B7-H1 mRNA in gastric cancer tissues. Mechanistically, miR-152 directly bind to B7-H1 3′ untranslated region in gastric cancer cell and inhibited B7-H1 expression. Functional study demonstrated that elevation of miR-152 enhanced T cells proliferation and effector cytokines production via inhibiting B7-H1/PD-1 pathway. In conclusion, our work identified a novel mechanism by which immune response is increased by expression of miR-152 via targeting B7-H1. MiR-152 may be a potential therapeutic approach for gastric cancer.