Human biliverdin reductase promotes EMT through the ERK1/2 signal pathway in breast cancer

Zhang, Min; Song, Shasha; Yi, Zhi; Zhao, Xin; Li, Fu; Wang, Lin; Ma, Cui; Mao, Min; Xing, Yan; Zhu, Daling

doi:10.1016/j.ejphar.2016.06.019

Cited by 15 publications

(16 citation statements)

References 41 publications

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“…Convincing evidence suggests that the EMT has a close relationship with metastasis and invasion of malignant tumor [40][41][42]. In the current study, we found that expression of CUL4A is significantly associated with the EMT.…”

Section: Discussionsupporting

confidence: 62%

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

Liao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cullin 4A (CUL4A) is vital in cell survival, development, growth and cell cycle, it plays an important role in chaperone-mediated ubiquitination and interacts with TP53 in carcinogenesis. However, the clinicopathologic significance of CUL4A expression in colorectal cancer is unknown; in particular, the prognostic value of CUL4A combined with TP53 expression has not been explored. Methods: We analyzed the expression of CUL4A in both public database (Oncomine) and 180 cases of colorectal cancer and paired normal tissues by real-time polymerase chain reaction and western blotting. Colony formation, wound healing, migration and invasion assays and tumorigenesis in nude mice were used to explore the function of CUL4A in CRC proliferation and metastasis in vitro and in vivo. Markers of epithelial to mesenchymal transition (EMT) were evaluated by western blotting. Immunohistochemistry (IHC) was used to analyse the relationship between CUL4A expression and E-cadherin expression. Results: CUL4A and TP53 protein expression was significantly higher in cancerous tissues compared to normal tissues. Significant correlation between CUL4A and TP53 expression was observed. CUL4A expression was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS). Interestingly, patients with tumors that had both CUL4A overexpression and mutant TP53 protein accumulation relapsed and died within a significantly short period after surgery (P < 0.001). Multivariate analysis showed that patients with both CUL4A+ and TP53+ positive tumors had extremely poor OS and DFS. Knockdown of CUL4A by a short interfering RNA (siRNA) significantly suppressed the progression of EMT, proliferation, migration, and invasion of colon cancer cells in vitro and tumor growth in vivo. ZEB1 silencing blocked CUL4A-driven these processes. Conclusion: CUL4A expression correlated positively with the prognosis of colorectal cancer. Mechanistically, ZEB1 was confirmed to mediate the function of CUL4A in regulating the EMT. The assessment of both CUL4A and mutant TP53 expression will be helpful in predicting colon cancer prognosis.

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Section: Discussionsupporting

confidence: 62%

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

Liao

et al. 2018

Cell Physiol Biochem

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“…20 In our CRC lines, BLVRA downregulated E-cadherin while it upregulated vimentin and snail, suggesting that it promoted EMT in CRC by Western blotting and immunofluorescence staining. This result was consistent with those of previous studies, in which BLVRA was shown to promote EMT in breast cancer 10 and NSCLC 7 by repressing E-cadherin expression. Our next step was the identification of the mechanism through which BLVRA exerted its actions in CRC cells.…”

Section: Discussionsupporting

confidence: 94%

“…These results were consistent with those of BLVRA knockdown studies in other malignancies. 7,10 Apoptosis, a conserved mechanism of programmed cell death, is malfunctioning in several cancers. Emerging evidence has shown that defective apoptosis not only promoted tumorigenesis but also brings about resistance of cancer cells to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…It also regulates the ERK1/2 signal pathway in breast cancer. 10 On the other hand, multiple signaling pathways are known to participate in CRC progression, including Wnt/β-catenin, PI3K/AKT/mTOR, and Notch. 23,24 The Wnt/β-catenin pathway is essential for development and Figure 5 The effects of BLVRA overexpression in SW620 cells (A) and BLVRA knockdown in HT-29 cells (B) on the levels of Wnt5a, total and phosphorylated β-catenin, and various proteins whose expression is controlled by the Wnt5a/β-catenin pathway, as assessed by Western blotting.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] Overexpression of BLVRA has been reported in many diseases, including cancers. The level of BLVRA is rather high in many cancers, including liver cancer, 6,9 lung cancer, 7 breast cancer, 10 skin cancer, 11 and esophageal cancer. 12 However, the role of BLVRA in CRC has not yet been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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<p>Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway</p>

Mao¹,

Xu²,

Zhang³

et al. 2020

CMAR

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Purpose: Biliverdin reductase A (BLVRA) is a pleiotropic enzyme that converts biliverdin-IX-alpha into the antioxidant and anti-nitrosative compound, bilirubin-IX-alpha. It is related to various diseases, including cancer. It is overexpressed in many types of cancers and promotes cancer development and metastasis, but the effects of BLVRA in colorectal cancer have not been researched at present. This study was aimed to investigate the effects of biliverdin reductase A (BLVRA) in vivo and vitro experiments and its possible mechanism. Methods: The clinical samples of CRC patients and CRC cell lines HT-29 and SW620 were chosen to perform the experiments. ELISA and Immunohistochemistry (IHC) were applied to test the level of BLVRA in patients. HT-29 knockdown of BLVRA and SW620 overexpression of BLVRA was established by the lentiviral vector transfection. Reverse transcription-quantitative real-time polymerase chain reaction and Western blotting were performed to examine the expression of BLVRA. MTT was used to detect the proliferation of CRC cells. Flow cytometry was applied to assess the rate of apoptosis. Transwell assay was performed to examine the capacity of migration and invasion. Immunofluorescence staining was adopted to assess the expression of E-cadherin and vimentin. Western blotting was utilized to detect the expression of apoptosis-related proteins, EMT-related proteins and target proteins of Wnt/β-catenin signaling pathway. Results: Analysis of the clinical samples revealed that BLVRA was overexpressed in CRC patients and implied poor prognosis. BLVRA overexpression in the in vitro studies revealed that it increased the potential of CRC cells for proliferation, migration and invasion; augmented EMT; and hindered apoptosis. In addition, BLVRA overexpression was found to upregulate positive target genes and downregulate negative target genes of the Wnt/β-catenin signaling pathway, which implied that the biological effects of BLVRA in CRC were mediated by this pathway. In contrast, knockdown of BLVRA manifested the opposite effects. Conclusion: Our results suggested that BLVRA might be a promising prognostic marker and a potential therapeutic target in CRC.

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Human biliverdin reductase regulates the molecular mechanism underlying cancer development

Zhang¹,

Wei²,

Yi³

et al. 2017

J of Cellular Biochemistry

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Human biliverdin reductase (hBVR), is an enzyme, that converts biliverdin to bilirubin, and has been implicated in epithelial-mesenchymal transition (EMT) in breast cancer. However, few studies have investigated the role of hBVR in cell apoptosis in other cancers. Therefore, the aim of this study was to investigate the effects of hBVR in several lines of cancer cells. The results of this study showed that hBVR expression was up-regulated in breast, lung, and liver cancers, but not ovarian cancer. Moreover, hBVR inhibition by small interfering RNA (si-hBVR) attenuated cell survival and increased caspase-3 protein expression, which was mediated by the ERK1/2 signaling pathway in relative cancer cells. In addition, the mitochondrial membrane potential and mitochondrial membrane proteins Bcl-2 and BAX were found to be necessary for activation of the mitochondria dependent apoptosis pathway. Collectively, these findings indicated, for the first time, that the anti-apoptotic effect of hBVR in cancers which portend new strategies for developing novel biomarkers and effective treatment ways for cancer patients.

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Human biliverdin reductase promotes EMT through the ERK1/2 signal pathway in breast cancer

Cited by 15 publications

References 41 publications

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

<p>Biliverdin Reductase A (BLVRA) Promotes Colorectal Cancer Cell Progression by Activating the Wnt/β-Catenin Signaling Pathway</p>

Human biliverdin reductase regulates the molecular mechanism underlying cancer development

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