Jinglong Wang

PD-1+ immune cell infiltration inversely correlates with survival of operable breast cancer patients

Abstract The programmed death-1 (PD-1) molecule is mainly expressed on functionally “exhausted” CD8+ T cells, dampening the host antitumor immune response. We evaluated the ratio between effective and regulatory T cells (Tregs) and PD-1 expression as a prognostic factor for operable breast cancer patients. A series of 218 newly diagnosed invasive breast cancer patients who had undergone primary surgery at Ruijin Hospital were identified. The influence of CD8+ cytotoxic T lymphocytes, FOXP3+ (Treg cell marker), and PD-1+ immune cell counts on prognosis was analyzed utilizing immunohistochemistry. Both PD-1+ immune cells and FOXP3+ Tregs counts were significantly associated with unfavorable prognostic factors. In bivariate, but not multivariate analysis, high tumor infiltrating PD-1+ cell counts correlated with significantly shorter patient survival. Our results suggest a prognostic value of the PD-1+ immune cell population in such breast cancer patients. Targeting the PD-1 pathway may be a feasible approach to treating patients with breast cancer.

Role of chemokine receptor CXCR7 in bladder cancer progression.

Bladder cancer is one of the most common tumors of the genitourinary tract; however, the molecular events underlying growth and invasion of the tumor remain unclear. Here, role of the CXCR7 receptor in bladder cancer was further explored. CXCR7 protein expression was examined using high-density tissue microarrays. Expression of CXCR7 showed strong epithelial staining that correlated with bladder cancer progression. In vitro and in vivo studies in bladder cancer cell lines suggested that alterations in CXCR7 expression were associated with the activities of proliferation, apoptosis, migration, invasion, angiogenesis and tumor growth. Moreover, CXCR7 expression was able to regulate expression of the proangiogenic factors IL-8 or VEGF, which may involve in the regulation of tumor angiogenesis. Finally, we found that signaling by the CXCR7 in bladder cancer cells activates AKT, ERK and STAT3 pathways. The AKT and ERK pathways may reciprocally regulate, which are responsible for in vitro and in vivo epithelial to mesenchymal transition (EMT) process of bladder cancer. Simultaneously targeting the two pathways by using U0126 and LY294002 inhibitors or using CCX733, a selective CXCR7 antagonist drastically reduced CXCR7-induced EMT process. Taken together, our data show for the first time that CXCR7 plays a role in the development of bladder cancer. Targeting CXCR7 or its downstream-activated AKT and ERK pathways may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for bladder cancer.

Dynamic response of pile groups embedded in a poroelastic medium

Abstract The dynamic response of pile groups embedded in a homogeneous poroelastic medium and subjected to vertical loading is considered. The piles are represented by compressible beam-column elements and the porous medium uses Biots three-dimensional elastodynamic theory. The dynamic impedance of pile groups can be computed directly by using pile–soil–pile dynamic interaction factors. The axial forces and pore pressures along the length of pile groups are computed by superposition method, which greatly reduces the computational time for the direct analysis of pile groups. Parametric studies are conducted for various conditions of pile groups. The superposition method is proposed for the dynamic response analysis of pile groups that is computationally feasible for practical applications.

HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification

Purpose: Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression. Experimental Design: The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests. Results: The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer–restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression. Conclusions: Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment. Clin Cancer Res; 19(6); 1400–10. ©2012 AACR.

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER+ breast cancer cells. Implications: Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer. Mol Cancer Res; 11(10); 1269–78. ©2013 AACR.

Transient foundation solution of saturated soil to impulsive concentrated loading

Abstract The transient dynamic response of saturated soil under suddenly applied normal and horizontal concentrated loading is studied in this paper. The behavior of saturated soil is governed by Biots consolidation theory. The general solutions for Biot equations of equilibrium are derived in terms of displacements and variations of fluid volume, using Laplace–Hankel integral transforms. The solutions in the time domain can be evaluated by numerical inverse Laplace–Hankel transforms. Selected numerical results for displacements, stresses, and pore pressures are presented. Comparisons with existing closed-form solutions for the elastic half-space are made to confirm the accuracy of the present solutions. The solutions can be used to study a variety of transient wave propagation problems and dynamical interactions between saturated soil and structures.

HIC1 Silencing in Triple-Negative Breast Cancer Drives Progression through Misregulation of LCN2

The tumor suppressor gene HIC1 is frequently deleted or epigenetically silenced in human cancer, where its restoration may improve cancer prognosis. Here, we report results illuminating how HIC1 silencing alters effect or signals in triple-negative breast cancer (TNBC), which are crucial for its pathogenesis. HIC1 expression was silenced only in TNBC compared with other molecular subtypes of breast cancer. Restoring HIC1 expression in TNBC cells reduced cell migration, invasion, and metastasis, whereas RNAi-mediated silencing of HIC1 in untransformed human breast cells increased their invasive capabilities. Mechanistic investigations identified the small-secreted protein lipocalin-2 (LCN2), as a critical downstream target of HIC1 in TNBC cells. Elevating LCN2 expression in cells expressing HIC1 partially rescued its suppression of cell invasion and metastasis. Notably, autocrine secretion of LCN2 induced by loss of HIC1 activated the AKT pathway through the neutrophil gelatinase-associated lipocalin receptor, which is associated with TNBC progression. Taken together, our findings revealed that the HIC1-LCN2 axis may serve as a subtype-specific prognostic biomarker, providing an appealing candidate target for TNBC therapy.

Retraction Note to: IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer

The authors wish to retract this article due to concerns raised regarding some of the data presented in Figures 2, 4, 5, 6 and Supplementary Figures 6 and 7. According to the data presented in Figures 1, 3 and 7, the major conclusion drawn from this article is still valid: IL-6 secreted by CAFs is causal factor for tamoxifen resistance in luminal breast cancer.

The feedback loop between miR-124 and TGF-β pathway plays a significant role in non-small cell lung cancer metastasis.

Increasing evidence shows that micro RNAs (miRNAs) play a critical role in tumor development. However, the role of miRNAs in non-small cell lung cancer (NSCLC) metastasis remains largely unknown. Here, we found that miR-124 expression was significantly impaired in NSCLC tissues and associated with its metastasis. In vitro and in vivo experiments indicate that restoring miR-124 expression in NSCLC cells had a marked effect on reducing cell migration, invasion and metastasis. Mechanistic analyses show that Smad4, a cobinding protein in transforming growth factor-β (TGF-β) pathway, was identified as a new target gene of miR-124. Restoring Smad4 expression in miR-124-infected cells could partially rescue miR-124-induced abolition of cell migration and invasion. Notably, upon TGF-β stimulation, phosphorylation of Smad2/3 was modulated by alteration of miR-124 or Smad4 expression, followed by inducing some special transcription of downstream genes including Snail, Slug and ZEB2, all of which may trigger epithelial-mesenchymal transition and be associated with NSCLC metastasis. Moreover, activation of TGF-β pathway may enhance expression of DNMT3a, leading to hypermethylation on miR-124 promoter. Therefore, heavily loss of miR-124 expression further enhances Smad4 level by this feedback loop. Taken together, our data show for the first time that the feedback loop between miR-124 and TGF-β pathway may play a significant role in NSCLC metastasis. Targeting the loop may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for NSCLC.

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple- negative breast cancer

BackgroundTissue inhibitor of metalloproteinases-1 (TIMP-1) is a multifunctional protein that can directly regulate apoptosis and metastasis. In this study, we investigated the functional and molecular mechanisms by which TIMP-1 influences triple-negative breast cancer (TNBC).MethodsThe expression level of TIMP-1 in breast cancer tissues was analyzed using the ONCOMINE microarray database. The overall survival of patients with distinct molecular subtypes of breast cancer stratified by TIMP-1 expression levels was evaluated using Kaplan–Meier analysis. Bisulfate sequencing PCR (BSP) was used to analyze the methylation status of the TIMP-1 promoter. Real-time-PCR (RT-PCR), Western blot and ELISA assays were used to evaluate gene and protein expression in cell lines and human tissue specimens. In addition, TIMP-1 function was analyzed using a series of in vitro and in vivo assays with cells in which TIMP-1 was inhibited using RNAi or neutralizing antibodies.ResultsWe found that serum TIMP-1 levels were strongly enhanced in patients with TNBC and that elevated TIMP-1 levels were associated with a poor prognosis in TNBC. However, TIMP-1 levels were not significantly associated with overall survival in other subtypes of breast cancer or in the overall population of breast cancer patients. We also report the first evidence that the TIMP-1 promoter is hypomethylated in TNBC cell lines compared with non-TNBC cell lines, suggesting that aberrant TIMP-1 expression in TNBC results from reduced DNA methylation. RNAi-mediated silencing of TIMP-1 in TNBC cells induced cell cycle arrest at the G1 phase and reduced cyclin D1 expression. In addition, mechanistic analyses revealed that the p-Akt and p-NF-κB signaling pathways, but not the GSK-3β and MAPK1/2 pathways, are associated with TIMP-1 overexpression in TNBC cells. Moreover, neutralizing antibodies against TIMP-1 significantly decreased the rate of tumor growth in vivo.ConclusionsOur findings suggest that TIMP-1 is a biomarker indicative of a poor prognosis in TNBC patients and that targeting TIMP-1 may provide an attractive therapeutic intervention specifically for triple-negative breast cancer patients.