Aberrant expression of genes and proteins in pterygium and their implications in the pathogenesis

Feng, Qing-Yang; Hu, Zixuan; Song, Xi-Ling

doi:10.18240/ijo.2017.06.22

Cited by 12 publications

(12 citation statements)

References 93 publications

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“…Pterygium refers to a group of conjunctival fibrovascular degenerations with diverse etiologies that resemble pre-squamous metaplasia and affect vision by progressively encroaching into the cornea. 53 – 55 Considering that (1) pterygium is associated with suppression of cyclin-dependent kinase inhibitor p21, 56 (2) BMP6 is upregulated in scarred conjunctival tissue 46 and its upregulation is associated with tumor aggressiveness, 57 and (3) the data presented thus far indicate that BMP6 regulates CE cell proliferation and differentiation in a cyclin- and p21-dependent manner, we tested whether or not BMP6 is altered in pterygium. RT-qPCR revealed significant upregulation of BMP6 transcripts coupled with significant downregulation of transcripts encoding cell cycle suppressors KLF4 and p21 , as well as Noggin , in pterygium tissues compared with the normal CE ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pterygium is a fibrovascular disease of the ocular surface with dysregulated cell proliferation and differentiation. 53 – 55 The increased levels of BMP6 in pterygium are contradictory to its role in normal CE, reminiscent of TGF-β having contradictory roles in normal and pathological conditions. 70 However, given that BMP6 regulates both proliferation and differentiation and is upregulated in different tumors and fibrotic conjunctival scars, 46 its increased expression in pterygium comes as no surprise.…”

Section: Discussionmentioning

confidence: 99%

“… 71 Previous reports of large-scale gene expression comparisons between pterygia and normal tissues failed to detect any change in BMP6 expression. 55 , 72 – 74 One potential reason for this is that pterygia with diverse etiologies display unique gene expression patterns. Thus, additional studies are needed to validate BMP6 involvement in pterygium.…”

Section: Discussionmentioning

confidence: 99%

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BMP6 Regulates Corneal Epithelial Cell Stratification by Coordinating Their Proliferation and Differentiation and Is Upregulated in Pterygium

Tiwari

Campbell

Jhanji

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Proper balance between cell proliferation and differentiation is essential for corneal epithelial (CE) stratification and homeostasis. Although bone morphogenetic protein-6 (BMP6) is known to be expressed in the CE for over 25 years, its function in this tissue remains unknown. Here, we test the hypothesis that BMP6 promotes CE cell stratification and homeostasis by regulating their proliferation and differentiation. METHODS. We employed postnatal day-12 (PN-12), PN-14, PN-20, and PN-90 mouse eyes; human corneal limbal epithelial (HCLE) cells; and ocular surface fibrovascular disease pterygium tissues to evaluate the role of BMP6 in CE proliferation, differentiation, and pathology by RT-qPCR, immunoblots, and/or immunofluorescent staining. Cell proliferation was quantified by immunostaining for Ki67. RESULTS. Coincident with the mouse CE stratification between PN-12 and PN-20, BMP6 was significantly upregulated and the BMP6 antagonist Noggin downregulated. Mature CE retained high BMP6 and low Noggin expression at PN-90. BMP6 and its receptors BMPR1A and BMPR2 were upregulated during in vitro stratification of HCLE cells. Consistent with its anti-proliferative role, exogenous BMP6 suppressed HCLE cell proliferation, downregulated cyclin-D1 and cyclin-D2, and upregulated cell-cycle inhibitors Krüppellike factor 4 (KLF4) and p21. BMP6 also upregulated the desmosomal cadherins desmoplakin and desmoglein in HCLE cells, consistent with its pro-differentiation role. Human pterygium displayed significant upregulation of BMP6 coupled with downregulation of Noggin and cell-cycle suppressors KLF4 and p21. CONCLUSIONS. BMP6 coordinates CE stratification and homeostasis by regulating their proliferation and differentiation. BMP6 is significantly upregulated in human pterygium concurrent with downregulation of Noggin, KLF4, and p21.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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BMP6 Regulates Corneal Epithelial Cell Stratification by Coordinating Their Proliferation and Differentiation and Is Upregulated in Pterygium

Tiwari

Campbell

Jhanji

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Our data suggested that HOXA5 inhibited the progression of GC. In order to further explore the underlying mechanisms, we used RT-qPCR to detect the expression of the following genes in 30 GC tissues, including tumorigenesis-related genes ( p21, p53 and β-catenin ), proliferation-related genes ( cyclin B1, cyclin D1, c-Myc and Ki67 ), angiogenesis-related genes [vascular endothelial growth factor ( VEGF ) A, VEGFR2 and epidermal growth factor ( EGFR )], metastasis-related genes [matrix metalloproteinase ( MMP2 ) and ( MMP7 )], apoptosis-related genes ( BCL2 and caspase-3 ), EMT markers (vimentin, N-cadherin and E-cadherin), stemness markers ( Lgr5, CD44 and EpCAM ) and multi-drug resistance genes ( ABCC1, ABCG2 and Beclin1) ( 10 – 15 ). A Spearman's correlation model was used to examine the correlation between each of these genes and HOXA5 mRNA expression.…”

Section: Resultsmentioning

confidence: 99%

HOXA5 is a tumor suppressor gene that is decreased in gastric cancer

et al. 2018

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The abnormal expression of homeobox A5 (HOXA5) has been observed in breast and colon cancer; however, the clinical significance of HOXA5 in gastric cancer (GC) is not yet clear. In this study, we found that HOXA5 expression was decreased in GC tissues at the mRNA and protein level compared with paracancerous tissues using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis, respectively. Immunohistochemistry and Kaplan-Meier survival analysis confirmed that the underexpression of HOXA5 was associated with GC progression and indicated a poor prognosis of patients with GC. Given that proliferation-related genes may be potential target genes of HOXA5, we performed a series of experiments in vitro to examine the effects of HOXA5 on the proliferation of GC cells. A CCK-8 assay, colony formation assay and flow cytometry revealed that HOXA5 inhibited the abnormal proliferation of GC cells, and this finding was further supported by a 5-ethynyl-2′-deoxyuridine (EdU) assay. Further mechanistic investigation clarified that HOXA5 promoted the protein expression of p21 and inhibited the protein expression of c-Myc and Ki67. Additionally, the use of nude mouse models also verified that HOXA5 suppressed the proliferation of GC cells in vivo. Collectively, the findings of this study demonstrate that HOXA5 acts as a tumor suppressor gene during the development and progresion of GC, possibly functioning by inhibiting the abnormal proliferation of cancer cells.

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“…Numerous studies have demonstrated the dysregulation of many genes in pterygium (Feng, Hu, Song & Pan, 2017). Inflammation can influence the expression of many genes at the transcriptional level via certain transcription factor, such as nuclear factor κB (NF-κB; Siak, Ng, Seet, Beuerman, & Tong, 2011).…”

Section: Introductionmentioning

confidence: 99%

Posttranscriptional regulation of MMP‐9 by HuR contributes to IL‐1β‐induced pterygium fibroblast migration and invasion

Cui

Feng

et al. 2019

Journal Cellular Physiology

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Inflammation is considered to be critical in the pterygium progression and recurrence. However, the underlying molecular mechanism is not well understood. Herein, we investigated the potential role of RNA binding protein human antigen R (HuR) responsible for the impact of inflammation on pterygium development. The expression of HuR and matrix metallopeptidase‐9 (MMP‐9) in pterygium and normal conjunctiva was detected with immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT‐PCR). The influence of interleukin‐1β (IL‐1β) on HuR expression and cellular distribution was determined with western blot and immunofluorescence. The pterygium fibroblast (PTF) migration was determined with scratch wound healing assay and Transwell migration assay. MMP‐9 production was determined with qRT‐PCR and gelatin zymography. The interaction between HuR and MMP‐9 was investigated with RNP immunoprecipitation (IP) followed by RT‐PCR and messenger RNA (mRNA) stability analysis. HuR and MMP‐9 expression are elevated in pterygium, especially progressive pterygium compared with normal conjunctiva. IL‐1β could increase the expression and nucleus–cytoplasm shuttle of HuR in cultured PTFs. HuR mediated the stimulatory effect of IL‐1β on PTF migration and MMP‐9 production. HuR bound to MMP‐9 mRNA and in turn increased it stability. Our results suggest that posttranscriptional regulation of MMP‐9 via stabilizing mRNA by HuR might contribute to the stimulatory effect of inflammatory factor IL‐1β on pterygium progression. These findings shed light on the pathogenesis of pterygium and provide a promising target for adjuvant treatment of pterygium.

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Aberrant expression of genes and proteins in pterygium and their implications in the pathogenesis

Cited by 12 publications

References 93 publications

BMP6 Regulates Corneal Epithelial Cell Stratification by Coordinating Their Proliferation and Differentiation and Is Upregulated in Pterygium

BMP6 Regulates Corneal Epithelial Cell Stratification by Coordinating Their Proliferation and Differentiation and Is Upregulated in Pterygium

HOXA5 is a tumor suppressor gene that is decreased in gastric cancer

Posttranscriptional regulation of MMP‐9 by HuR contributes to IL‐1β‐induced pterygium fibroblast migration and invasion

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