αB-Crystallin, an Effector of Unfolded Protein Response, Confers Anti-VEGF Resistance to Breast Cancer via Maintenance of Intracrine VEGF in Endothelial Cells

Ruan, Qiurong; Han, Song; Jiang, Wen Guo; Boulton, Michael E.; Chen, Zhi J.; Law, Brian K.; Cai, Jun

doi:10.1158/1541-7786.mcr-11-0327

Cited by 57 publications

(74 citation statements)

References 40 publications

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“…In human endometrium, Cryab expression is upregulated during the window of implantation (Gruidl et al 1997), which further supported a role for Cryab in implantation. Additional studies have found that Cryab could regulate angiogenesis by modulating the expression of vascular endothelial growth factor (VEGF), which was the main factor responsible for increased endometrial vascular permeability at implantation (Rabbani & Rogers 2001, Rockwell et al 2002, Kase et al 2010, Ruan et al 2011. Inhibition of VEGF could significantly reduce the number of implantation sites (Rabbani & Rogers 2001, Rockwell et al 2002, Guo et al 2012.…”

Section: Discussionmentioning

confidence: 99%

Differential expression and regulation of Cryab in mouse uterus during preimplantation period

Tian¹,

Wang²,

Li³

et al. 2013

Reproduction

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The aim of this study was to examine the expression and regulation of the crystallin, alpha B (Cryab) gene in mouse uterus during the peri-implantation period by in situ hybridization and real-time PCR. There was no detectable Cryab mRNA signal on days 1-4 of pregnancy. On day 5 of pregnancy when embryo implanted, a high level of Cryab mRNA signal was found in the subluminal stroma surrounding the implanting blastocyst. On days 6-8, Cryab mRNA was strongly expressed in the primary decidua. By real-time PCR, a high level of Cryab expression was detected on days 7 and 8 of pregnancy, although Cryab expression was seen from days 1 to 8. Under in vivo and in vitro artificial decidualization, Cryab expression was significantly elevated. Compared with the progesterone-primed delayed implantation uterus, a high level of Cryab mRNA expression was observed in estrogen-activated implantation uterus. In the uterine stromal cells, cAMP, estrogen, and progesterone could induce the expression of Cryab gene. In the ovariectomized mouse uterus, estrogen could also induce the expression of Cryab while progesterone inhibited its expression. Our data suggest that Cryab may play an important role during mouse embryo implantation and decidualization and that estrogen and progesterone can regulate the expression of Cryab gene.

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Section: Discussionmentioning

confidence: 99%

Differential expression and regulation of Cryab in mouse uterus during preimplantation period

Tian¹,

Wang²,

Li³

et al. 2013

Reproduction

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“…33,39 Upregulation of CryaB in ECs was shown to confer anti-VEGF resistance in cancer cells, suggesting that CryaB inhibition may function in addition to anti-VEGF in therapies. 40 Regulation of CryaB by miR-126-3p suggests that miR-126-3p may have therapeutic implications in other CryaB-related diseases than AMD, including cancer and neurodegenerative diseases. Although RPE cells from CryaB −/− mice shown increased death under oxidative stress, CryaB downregulation by miR-126-3p did not cause RPE cell death (Supplementary Figure S7), suggesting the safety of targeting CryaB using miR-126-3p mimic.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis

et al. 2016

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microRNAs or miRs have been shown to be pivotal modulators of vascular development. The strand and cell typespecific function of miR-126 in angiogenesis, especially pathological angiogenesis, remains poorly defined. We characterized the retinal vascular phenotype of miR-126 −/− mice, and tested the function of miR-126 strands (miR-126-3p and -5p) using in vitro angiogenesis models and a mouse model of neovascular age-related macular degeneration. We found that miR-126 is critical for retinal vascular development but has dual function in pathological angiogenesis. miR-126 −/− mice showed defective postnatal retinal vascular development and remodeling, which is partially rescued by genetic knockout of its target gene Spred-1. Surprisingly, either silencing miR-126-3p by LNA-antimiR or overexpressing miR-126-3p by miRNA mimic repressed laser-induced choroidal neovascularization. To dissect the underlying mechanism, we found in endothelial cells, silencing of miR-126-3p repressed angiogenesis, while overexpression of miR-126-5p enhanced angiogenesis. However, in retinal pigment epithelial cells, miR-126-3p repressed vascular endothelial growth factor (VEGF-A) expression via a novel mechanism of regulating αB-Crystallin promoter activity and by directly targeting VEGF-A 3′-untranslated region. These findings provide first genetic evidence that miR-126 is required for the development of different retinal vascular layers, and also uncover a strand and cell type-specific function of miR-126 in ocular pathological angiogenesis. Received 17 March 2016; accepted 11 May 2016; advance online publication 21 June 2016 advance online publication 21 June . doi:10.1038 advance online publication 21 June /mt.2016 INTRODUCTIONThe retina has been an excellent model to study developmental and pathological angiogenesis. Vascularization of the mouse outer retina occurs through two waves of angiogenesis after birth, when endothelial cells (ECs) sprout from the central retinal artery to the peripheral region and then to the intermediate and deep layers of the retinal vascular plexus.1,2 Pathological angiogenesis in the eye is the most common cause of blindness at all ages and underlies conditions such as retinopathy of prematurity in children, diabetic retinopathy in young adults and age-related macular degeneration (AMD) in the elderly. AMD is a degenerative disease of the retina and the leading cause of blindness among the elderly.3 Neovascular (or wet) AMD, which accounts for the majority of acute vision loss in AMD, is characterized by choroidal neovascularization (CNV), a process involving abnormal growth of blood vessels from the choroid into the retina. Vascular endothelial growth factor (VEGF), which is highly expressed in the retinal pigment epithelial (RPE) cells in the eye, is a major cytokine driving neovascularization and vascular permeability during CNV. Several FDA-approved anti-VEGF agents, including Macugen, Lucentis and Eylea, are the current mainstay for wet AMD treatment. 4-6Although anti-VEGF agents have marked...

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“…Additional genes of interest such as RAD51, EGFR, ERBB2, and CRYAB were also included [35,[39][40][41][42]. The complete gene list can be found in Supplementary Table 1.…”

Section: Gene Expression Profiles Gene Selection and Probe Designmentioning

confidence: 99%

Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).

Barry¹,

Li-Chang²,

Kennecke³

2015

JCO

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A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6mg/kg IV q2weeks. Of 34 panitumumabtreated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders.A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities.This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.

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αB-Crystallin, an Effector of Unfolded Protein Response, Confers Anti-VEGF Resistance to Breast Cancer via Maintenance of Intracrine VEGF in Endothelial Cells

Cited by 57 publications

References 40 publications

Differential expression and regulation of Cryab in mouse uterus during preimplantation period

Differential expression and regulation of Cryab in mouse uterus during preimplantation period

Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis

Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).

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