Κυριακή, 7 Απριλίου 2019

Anatomy Pathology

Sat Apr 06, 2019 15:39
 CBP/p300 antagonises EGFR‐Ras‐Erk signalling and suppresses increased Ras‐Erk signalling‐induced tumour formation in mice

Abstract

CBP and p300 have oncogenic properties; both cooperate with pro‐oncogenic transcription factors downstream of Ras‐Erk signalling to support cell proliferation. By contrast, missense, truncating and in‐frame mutations of CBP/p300 are found frequently in some human cancers, including cutaneous squamous cell carcinomas that originate from epidermal keratinocytes. Data support that dysfunction of CBP/p300 contributes to keratinocyte hyperproliferation and tumourigenesis; however, the mechanism by which dysfunction of CBP/p300 affects keratinocytes is unknown. Here, we used mice harbouring keratinocyte‐specific genetic modifications to examine the role of CBP/p300 in the epidermis. While a single copy of either Crebbp or Ep300 was necessary and sufficient for maintaining epidermal development, reduced expression of CBP/p300 strengthened the Ras‐Erk signalling‐induced hyperplastic phenotype of epidermal keratinocytes. Reduced CBP/p300 expression increased ligand‐induced EGFR activity while decreasing basal expression of Mig6, a negative regulator of EGFR. Reduction of CBP/p300, in combination with increased Ras‐Erk signalling, also promoted epidermal tumour formation in mice. Thus, our findings support that CBP/p300 acts as a tumour suppressor in epidermal keratinocytes by counteracting EGFR‐Ras‐Erk signalling.

Fri Apr 05, 2019 21:59
 Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

Abstract

Mesenchymal glioblastoma is the most aggressive subtype of glioblastoma (GBM). Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal glioblastoma is still unclear. In this study, bioinformatic analysis, western blotting and RT‐qPCR were used to detect the expression of PSAP in different GBM subtypes. The human glioma cell lines and patient derived glioma stem cells were studies in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote glioblastoma invasion and epithelial‐mesenchymal transition (EMT) ‐like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in glioblastoma invasion and EMT‐like process via the TGF‐β1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM.

Wed Apr 03, 2019 19:00
 Bone marrow‐derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells

Abstract

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high‐fat/high‐cholesterol (HFHC) or methionine‐and‐choline‐deficient (MCD) diet. Bone marrow transplantation (BMT) was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human non‐alcoholic steatohepatitis (NASH)‐fibrosis patients. Bone marrow‐derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro‐fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro‐fibrotic factors (TIMP1, TIMP2 and TGFβ1) and endoplasmic reticulum (ER) stress markers (GRP78, IRE1α and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage‐conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX‐2 and HSC‐T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro‐fibrosis factors and signaling pathways including cytokine/chemokine, TGFβ, and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti‐fibrotic macrophages and decreasing pro‐fibrotic macrophages are promising approaches for fibrosing steatohepatitis.

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Wed Apr 03, 2019 17:51
 YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo‐/radio‐resistance by suppressing caspase‐mediated apoptosis

Abstract

The objective of this study was to characterize the oncogenic actions of a recently identified cancer‐associated gene YWHAZ (also named as 14‐3‐3 ζ/δ) in urothelial carcinomas of the urinary bladder (UCUB). A genome‐wide study revealed YWHAZ to be involved in the amplicon at 8q22.3, and its genetic amplification was detected predominantly in muscle‐invasive bladder cancer (MIBC). Immunohistochemical staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis (GSEA) and STRING network studies suggested involvement of YWHAZ in regulating caspase‐mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low endogenous YWHAZ levels boosted cell resistance to doxorubicin and cisplatin, as well as to ionizing radiation. Conversely, YWHAZ‐knockdown using specific shRNA in cells with high endogenous YWHAZ levels diminished survival activity, suppressing cell growth and increasing cell death. Our findings confirm the essential role played by YWHAZ in sustaining cell proliferation during chemo/radiotherapy. Treatments based on anti‐YWHAZ strategies may thus be beneficial for UCUB patients overexpressing YWHAZ.

This article is protected by copyright. All rights reserved.


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