The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT þ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNg production, whereas CD155 overexpression inhibited T-cell metabolism and IFNg production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice.Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer.

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Mechanical overload can be classified into pressure overload and volume overload, causing concentric and eccentric cardiac hypertrophy, respectively. Here, we aimed to differentiate the load-mediated signaling pathways involved in pressure versus volume overload cardiac hypertrophy. Pressure or volume overload was imposed on C57BL/6J mice by transverse aortic constriction (TAC) or aortic regurgitation (AR), respectively. After surgery (2 wk), left ventricular structure and function were evaluated by echocardiographic, hemodynamic, and histological analyses. Signaling pathways related to hypertrophy, fibrosis, angiogenesis, and apoptosis were studied by histological analysis, RT-PCR, and Western blot analysis. Although mean wall stress was similar in both TAC and AR mice, systolic wall stress was significantly increased in TAC and diastolic wall stress was mainly elevated in AR. TAC or AR induced concentric or eccentric compensated hypertrophy, respectively. TAC was associated with more significant fibrosis and apoptosis, whereas AR was associated with more significant angiogenesis. MAPK kinase family, β-arrestin-2, Akt, and Ca-related signaling pathways were markedly activated in TAC but mildly upregulated or unchanged in AR. Pressure overload and volume overload induce different phenotypic and molecular adaptations in cardiac hypertrophy. Most load-related signaling pathways assessed in this study predominate in pressure but not volume overload. The stimulus-specific heterogeneity in the signaling pathways requires distinct manipulations for further mechanistic and pharmacological studies. NEW & NOTEWORTHY Using the transverse aortic constriction mouse model and the newly developed aortic regurgitation mouse model, we delineated the prominent differences between concentric and eccentric cardiac hypertrophy on morphological, functional, and molecular levels. Our findings are important for the precise diagnosis and treatment of these two types of cardiac hypertrophy. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chinese-english-language-podcast-on-differential-cardiac-remodeling-in-tac-vs-ar/ .

BackgroundThe primary obstacle to treat cervical cancer is its high prevalence of metastasis, which severely affects patients’ quality of life and survival time. Nucleolar and spindle associated protein 1 (NUSAP1) has been implicated in the development, progression, and metastasis in several types of cancer. However, its oncogenic role in cervical cancer remains unclear.MethodsWestern blot assay and immunohistochemistry were used to determine the expression of NUSAP1 in 21 clinical fresh Cervical cancer tissues and 233 clinicopathologically characterized cervical cancer specimens. The biological roles of NUSAP1 in the metastasis of cervical cancer were investigated both in vitro by EMT, Side population analysis and Transwell assays and so on, and in vivo using a mouse 4w model of hematogenous metastasis and lymph node metastasis. Bioinformatics analysis, luciferase reporter analysis, immunoprecipitation and immunoblotting of nuclear and cytoplasmic cellular fractions were applied to discern and examine the relationshipbetween NUSAP1 and its potential targets.ResultsThe results demonstrated that NUSAP1 was upregulated in cervical cancer cells and tissues, correlated positively with metastasis and poor clinical outcome of patients. High expression of NUSAP1 promoted metastasis by enhancing cancer stem cell (CSC) traits and epithelial-mesenchyme transition (EMT) progression, while silencing of NUSAP1 reduced CSC traits and EMT progression. Mechanistically, upregulation of NUSAP1 induced SUMOylation of TCF4 via interacting with SUMO E3 ligase Ran-binding protein 2 (RanBP2) and hyperactivated Wnt/β-catenin signaling in cervical cancer cells. Additionally, NUSAP1-induced cervical cancer cells metastasis and the cancer stem cell phenotype were abrogated with the Wnt/β-catenin signaling inhibitor XAV-939 treatment. Importantly, co-therapy of conventional treatment and XAV-939 will provide a novel and effective treatment for NUSAP1-ovexpressed cervical cancer patients.ConclusionsOur results demonstrate thatNUSAP1 upregulation contributes to metastasis of cervical cancer by promoting CSC properties and EMT via Wnt/β-catenin signaling and XAV-939 might serve as a potential tailored therapeutic option for patients with NUSAP1-ovexpressed cervical cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1037-y) contains supplementary material, which is available to authorized users.

Musashi-2 (Msi2) is considered to have a crucial role in regulating various key cellular functions. However, the clinical significance and biological role of Msi2 in bladder cancer remains unknown. We examined the expression of Msi2 in bladder cancer cell lines in 167 clinical samples and the biological role of Msi2 in bladder cancer cells. Western blotting was used to investigate the possible mechanism of Msi2-induced migration and invasion in bladder cancer. Msi2 was significantly upregulated in bladder cancer cells and tissues compared with normal bladder urothelial cells and tissues. Immunohistochemical analysis revealed high expression of Msi2 in 57 of 167 (34.1%) bladder cancer specimens. Statistical analysis showed a significant correlation of Msi2 expression with advanced clinical stage, lymph node metastasis, and poor prognosis. Overexpression and ablation of Msi2 promoted and inhibited, respectively, the migration and invasion of bladder cancer cells. Furthermore, we found that Msi2 activated the JAK2/STAT3 pathway and promoted expression of genes downstream of JAK2/STAT3 in bladder cancer. This study demonstrates that Msi2 can induce bladder cancer cell migration and invasion by activating the JAK2/STAT3 pathway, and that Msi2 may be a valuable prognostic biomarker for bladder cancer patients.Laboratory Investigation (2016) 96, 950-958;

BackgroundThe aim of this study was to elucidate the value of putative cancer stem cell markers Musashi-1, ALDH1, Sox2, and CD49f in predicting the prognosis in cervical squamous cell carcinoma (CSCC).MethodsReal-time PCR and immunohistochemistry staining was performed to examine Musashi-1, ALDH1, Sox2, and CD49f expression in archived specimens of CSCC patients with postoperative chemotherapy. Kaplan–Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of CSC markers for overall survival (OS) and recurrent-free survival (RFS).ResultsThe Real-time PCR data showed that the expression of all markers were increased in CSCC tissues compared with in paired normal cervical tissues (P < 0.05). The IHC result showed that high expression of Msi1, ALDH1, Sox2, and CD49f was found in 25.7 %, 43.0 %, 62.0 % and 29.0 % CSCC samples, respectively. Moreover, high expression of Msi1 (P = 0.033 and P = 0.003, respectively), ALDH1 (P = 0.015 and P = 0.002, respectively), and Sox2 (P = 0.005 and P = 0.003, respectively), and low expression of CD49f (P = 0.027 and P = 0.025, respectively) were correlated with poor OS and PFS in CSCC patients. Interestingly, tumors with Msi1high/CD49flow expression had the poorest prognosis according to Msi1/CD49f stratification. In multivariate Cox regression analysis, Sox2 expression (P = 0.047 and P = 0.018, respectively), ALDH1 expression (P = 0.013 and P = 0.003, respectively), and CD49f expression (P = 0.008 and P = 0.003, respectively) were independent prognostic markers for both OS and RFS.ConclusionsOur results suggest that cancer stem cell markers are linked with poor prognosis of CSCC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1826-4) contains supplementary material, which is available to authorized users.

Primary breast diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB‐DLBCL patients. We retrospectively reviewed data on 108 PB‐DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow‐up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5‐year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5‐year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10‐year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB‐DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB‐DLBCL patients.

BackgroundThe kinesin family member 20a (KIF20A) protein has been implicated in the development and progression of many human cancers; however, its precise function and role in cervical cancer remain largely unclear. This study aimed to investigate the expression profile and prognostic value of KIF20A in patients with early-stage cervical squamous cell carcinoma.MethodsWe examined the mRNA and protein levels of KIF20A in eight cervical cancer cell lines and eight paired cervical cancer samples, compared with normal cervical epithelial cells and adjacent normal cervical tissues, respectively. Immunohistochemistry was performed to detect the expression of KIF20A in paraffin-embedded specimens from 169 early-stage cervical squamous cell carcinoma patients. Statistical analyses were applied to analyze the association between KIF20A expression and clinical variables, as well with patient survival.ResultsThe mRNA and protein expression levels of KIF20A were significantly elevated in cervical cancer cell lines and lesions compared with normal cells and corresponding normal tissues (P < 0.05). Immunohistochemistry analysis in 169 cervical cancer cases revealed that increased KIF20A expression was strongly associated with human papillomavirus (HPV) infection (P = 0.008), clinical stage (P = 0.001), tumor recurrence (P = 0.016), vital status (P < 0.001), the property of the surgical margin (P = 0.032), the lymphovascular space involvement (P = 0.014), and pelvic lymph node metastasis (P = 0.001). The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression. KIF20A was an independent survival prognostic factor, as evidenced by univariate and multivariate analysis.ConclusionsOur results illustrate that elevated KIF20A expression correlates with HPV infection, clinical stage, tumor recurrence, lymphovascular space involvement, pelvic lymph node metastasis, and poor outcome in early-stage cervical squamous cell carcinoma patients. KIF20A aberrant expression is a novel independent unfavorable prognostic factor and may present a potential therapeutic target for cervical cancer.