Clinical and <i>in vitro</i> analysis of Osteopontin as a prognostic indicator and unveil its potential downstream targets in bladder cancer

Wong, Janet Pik Ching; Wei, Ran; Lyu, Peng; Tong, Olivia; Zhang, Shudong; Wen, Qing; Yuen, Hiu Fung; El‐Tanani, Mohamed; Kwok, Hang Fai

doi:10.7150/ijbs.21457

Cited by 27 publications

(27 citation statements)

References 61 publications

(83 reference statements)

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“…It has been well known that OPN overexpression has enhanced tumour behaviour, but the potential co‐regulation genes involved in this complex process have not been well identified. In our previous work, we have shown that the expression of OPN and MMP9 were positively correlated in human bladder cancer specimens and bladder cancer cell lines . In the present study, we found that overexpression of OPN up‐regulated MMP9 while OPN and MMP9 expression levels were positively correlated in two independent colon cancer datasets.…”

Section: Discussionsupporting

confidence: 68%

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In vitro and clinical data analysis of Osteopontin as a prognostic indicator in colorectal cancer

Wei

Wong

Lyu

et al. 2018

J Cellular Molecular Medi

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Osteopontin (OPN) has been shown to promote colorectal cancer (CRC) progression; however, the mechanism of OPN‐induced CRC progression is largely unknown. In this study, we found that OPN overexpression led to enhanced anchorage‐independent growth, cell migration and invasion in KRAS gene mutant cells but to a lesser extent in KRAS wild‐type cells. OPN overexpression also induced PI3K signalling, expression of Snail and Matrix metallopeptidase 9 (MMP9), and suppressed the expression of E‐cadherin in KRAS mutant cells. In human CRC specimens, a high‐level expression of OPN significantly predicted poorer survival in CRC patients and OPN expression was positively correlated with MMP9 expression, and negatively correlated with E‐cadherin expression. Furthermore, we have found that 15 genes were co‐upregulated in OPN highly expression CRC and a list of candidate drugs that may have potential to reverse the secreted phosphoprotein 1 (SPP1) gene signature by connectivity mapping. In summary, OPN is a potential prognostic indicator and therapeutic target for colon cancer.

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Section: Discussionsupporting

confidence: 68%

“…The p3XFLAG‐CMV‐7.1 (Sigma, E7533) was ligated to the N‐terminal of OPN‐c gene of pcDNA3‐OPN‐V5, which was a gift from Steven Johnson (Addgene plasmid # 11617) . Then it was inserted into pBABE‐puro which was a gift from Hartmut Land, Jay Morgenstern and Bob Weinberg (Addgene plasmid # 1764) .…”

Section: Methodsmentioning

confidence: 99%

In vitro and clinical data analysis of Osteopontin as a prognostic indicator in colorectal cancer

Wei

Wong

Lyu

et al. 2018

J Cellular Molecular Medi

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“…Regarding BCa, immunohistochemical staining of OPN demonstrated significant correlation with tumor stage (27). More recently, Wong and colleagues showed that OPN expression correlates with disease stage and grading and that higher OPN expression led to decreased survival in multiple patient cohorts (26). Of note, we could not see the same in our TCGA data set when applying median expression for overall and diseasefree survival (Supplementary Figure 9).…”

Section: Nrp2 Positively Regulates Osteopontin Expressionmentioning

confidence: 69%

“…However, only one gene transcript was regulated in a similar manner to NRP2 knockout in RT112 as well as NRP2 knockdown in J82 ( Figure 6C). The SPP1 gene (Osteopontin, OPN) was previously reported to be induced by VEGF (25) and to be associated with decreased survival, disease stage, and grading in BCa (26,27). Previous findings support the role of SPP1 as one of the key EMT regulators (28).…”

Section: Knockout Of Nrp2 Alters Gene Expression Of Emt Regulatorsmentioning

confidence: 75%

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

et al. 2020

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Neuropilin-2 (NRP2) is a prognostic indicator for reduced survival in bladder cancer (BCa) patients. Together with its major ligand, vascular endothelial growth factor (VEGF)-C, NRP2 expression is a predictive factor for treatment outcome in response to radiochemotherapy in BCa patients who underwent transurethral resection. Therefore, we investigated the benefit of combining cisplatin-based chemotherapy with irradiation treatment in the BCa cell line RT112 exhibiting or lacking endogenous NRP2 expression in order to evaluate NRP2 as potential therapeutic target. We have identified a high correlation of NRP2 and the glioma-associated oncogene family zinc finger 2 (GLI2) transcripts in the cancer genome atlas (TCGA) cohort of BCa patients and a panel of 15 human BCa cell lines. Furthermore, we used in vitro BCa models to show the transforming growth factor-beta 1 (TGFβ1)-dependent regulation of NRP2 and GLI2 expression levels. Since NRP2 was shown to bind TGFβ1, associate with TGFβ receptors, and enhance TGFβ1 signaling, we evaluated downstream signaling pathways using an epithelial-to-mesenchymal transition (EMT)-assay in combination with a PCR profiling array containing 84 genes related to EMT. Subsequent target validation in NRP2 knockout and knockdown models revealed secreted phosphoprotein 1 (SPP1/OPN/Osteopontin) as a downstream target positively regulated by NRP2.

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“…Fouad et al [15] revealed that MMP-9 was significantly up-regulated in both blood and urine of BCa patients and was of great discriminatory ability in the diagnosis of BCa. Wong et al [16] also demonstrated that MMP9 was a potential therapeutic target and prognostic biomarker that contribute to the progression of BCa. There have been several studies confirming the role of IGF-1, an anti-apoptotic peptide, in the progression of BCa.…”

Section: Discussionmentioning

confidence: 98%

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

Lin

et al. 2020

Cancer Cell Int

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Background: Bladder cancer (BCa) is one of the important tumors that have been proven to be treatable with immunotherapy. This study aims to identify and validate a molecular prognostic index of BCa based on immunogenomic landscape analysis. Methods: The cancer genome atlas (TCGA) database and immunology database and analysis portal (ImmPort) database were used to identified differentially expressed immune-related genes (IRGs). Prognostic IRGs were screened and protein-protein interaction (PPI) network was constructed. Multivariate Cox analysis was performed to develop a molecular prognostic index of BCa. Internal and external validation were then performed in TCGA cohort and GEO cohort, respectively. Besides, we also explore the relationship between this index and clinical characteristics, immune cell infiltration and tumor microenvironment. Results: A total of 61 prognostic IRGs were identified and a molecular prognostic index was developed. The top four hub genes included MMP9, IGF1, CXCL12 and PGF. The difference in overall survival between high-risk group and low-risk group was statistically significant. The area under curve of the receiver operating characteristic (ROC) curve was 0.757, suggesting the potential for this index. Besides, Internal validation using TCGA cohort and external validation using GEO cohort indicated that this index was of great performance in predicting outcome. T cells CD8, T cells CD4 memory activated, T cells follicular helper, macrophages M0, macrophages M2 and neutrophils were significantly associated with prognosis of BCa patients. Female, high grade, stage III&IV, N1-3 and T3-4 were associated significantly with higher risk score compared with male, low grade, stage I&II, N0 and T1-2, respectively. High risk score had a positive association with higher stromal score and ESTIMATE score while high risk score had a negative association with tumor purity. Conclusions: This study identified several prognostic immune-related genes of clinical value. Besides, we developed and validated a molecular index based on immunogenomic landscape analysis, which performed well in predicting prognosis of BCa. Further researches are needed to verify the effectiveness of this index and these vital genes.

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Clinical and in vitro analysis of Osteopontin as a prognostic indicator and unveil its potential downstream targets in bladder cancer

Cited by 27 publications

References 61 publications

In vitro and clinical data analysis of Osteopontin as a prognostic indicator in colorectal cancer

In vitro and clinical data analysis of Osteopontin as a prognostic indicator in colorectal cancer

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

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