AGR2 is a target of canonical Wnt/β-catenin signaling and is important for stemness maintenance in colorectal cancer stem cells

Lamichane, Babita Dahal; Jung, Sun Young; Yun, Jisoo; Kang, Su-Tae; Kim, Da Yeon; Lamichane, Shreekrishna; Kim, Yeon Ju; Park, Ji Hye; Jang, Woong Bi; Ji, Seung Taek; Li, Dehua; Ha, Jong Seong; Kim, Yun Hak; Kwon, Sang‐Mo

doi:10.1016/j.bbrc.2019.05.154

Cited by 35 publications

(24 citation statements)

References 20 publications

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“…The discovered mechanism of Twist1-mediated upregulation of AGR2 seems especially important as it is AGR2 that is required for Twist1-induced activation of breast tumor cell migration and invasion, which are associated with cancer stemness [268]; thus, the AGR2-Twist1 axis should be considered as one of the endogenous drivers in cancer stemness development. There were findings indicating the implication of ARG2 in maintaining the stem phenotype in colorectal CSCs in which this chaperone has been identified as a stem cell marker [269]. In this study, Wnt/β-catenin pathway-regulated AGR2 expression was shown to be correlated with the expression of known cell surface stem markers as well as with the cell spheroid-forming capacity [269].…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 60%

“…There were findings indicating the implication of ARG2 in maintaining the stem phenotype in colorectal CSCs in which this chaperone has been identified as a stem cell marker [269]. In this study, Wnt/β-catenin pathway-regulated AGR2 expression was shown to be correlated with the expression of known cell surface stem markers as well as with the cell spheroid-forming capacity [269]. Other researchers have demonstrated that AGR3 is also implicated in stemness development/maintenance in colorectal cancer via AGR3-mediated modulating of the Wnt/β-catenin signaling pathway; notably, these stemness-promoting and Wnt/β-catenin pathway-modulating activities of AGR3 were dependent on the presence of frizzled 4 (FZD4), a G-protein-coupled receptor for Wnt proteins [270].…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

“…Other researchers have demonstrated that AGR3 is also implicated in stemness development/maintenance in colorectal cancer via AGR3-mediated modulating of the Wnt/β-catenin signaling pathway; notably, these stemness-promoting and Wnt/β-catenin pathway-modulating activities of AGR3 were dependent on the presence of frizzled 4 (FZD4), a G-protein-coupled receptor for Wnt proteins [270]. It seems rather intriguing that the development and maintenance of cancer stemness may be based on the FZD4-dependent regulatory axis involving two protein disulfide isomerases (AGR3-Wnt/β-catenin signaling-AGR2), as it follows from the studies performed on colorectal cancer [269,270]; at least, this may provide additional opportunities for he therapeutic targeting of cancer stemness. Extracellular (secreted) protein disulfide isomerases may also promote the stemness-associated activities of cancer cells.…”

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Section: Protein Disulfide Isomerasesmentioning

confidence: 60%

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

Section: Protein Disulfide Isomerasesmentioning

confidence: 99%

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Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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“…19 Recently, anterior gradient protein-2 (AGR2), an androgen-regulated gene, has been identified as an oncogene and generally overexpressed in various cancers. [20][21][22][23] AGR2 promotes the metastasis of breast cancer cells. 21 Besides, High AGR2 expression has been reported to show lower overall survival of CRC patients.…”

Section: Discussionmentioning

confidence: 99%

<p>Long Noncoding RNA LINC00460 Promotes Hepatocellular Carcinoma Progression via Regulation of miR-342-3p/AGR2 Axis</p>

Yang¹,

Li²,

Chen³

et al. 2020

OTT

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Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. LINC00460, a novel long non-coding RNA (lncRNA), was recently confirmed as an oncogene in various cancers. However, the biological function and underlying mechanism of LINC00460 in HCC is largely obscure. Methods: Fifty pairs of tumor tissue and adjacent normal tissues from HCC patients, as well as six HCC cell lines and a normal human hepatic epithelial cell line were subjected to qRT-PCR assay to evaluate the expression levels of LINC00460. CCK-8 assays were used to detect the proliferation of HCC cells. Transwell assay was used to measure the migration and invasion abilities of HCC cells. RNA pull-down and luciferase assays were performed to verify the direct interaction between LINC00460 and miR-342-3p. A xenograft model of HCC was established to validate the in vivo function of LINC00460 in HCC progression. Results: We firstly detected LINC00460 expression was significantly upregulated in both HCC tumor tissues and cell lines. The upregulation of LINC00460 was positively associated with HCC progression. Functionally, LINC00460 facilitated HCC cell proliferation, migration, and invasion capacities, which due to that LINC00460 could physically bind to and repress miR-342-3p to elevate the expression of AGR2. Conclusion: Our data firstly reveal the clinical relevance, biological function, and regulatory mechanism of LINC00460 in HCC development. LINC00460 promotes HCC progression by elevating AGR2 expression via sponging miR-342-3p, providing a promising therapeutic target for HCC treatment.

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“…27,28 Canonical Wnt/β-catenin signaling is also directly linked to its extracellular secretion for tumor progression of colon CSCs. 29 In this pathway, without Wnt, β-catenin cannot accumulate in the cytoplasm as it is phosphorylated by glycogen synthase kinase 3-beta (GSK3β), then ubiquitinated and degraded by the proteasome. In the presence of Wnt, the stable, non-phosphorylated β-catenin enters the nucleus to form an active complex with lymphoid enhancer factor (LEF) and T-cell factor (TCF), thus leading to the transcriptional activation of β-catenin target genes such as the cyclin D1, c-Myc, cox-2, PTEN, and survivin.…”

Section: Discussionmentioning

confidence: 99%

<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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AGR2 is a target of canonical Wnt/β-catenin signaling and is important for stemness maintenance in colorectal cancer stem cells

Cited by 35 publications

References 20 publications

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

<p>Long Noncoding RNA LINC00460 Promotes Hepatocellular Carcinoma Progression via Regulation of miR-342-3p/AGR2 Axis</p>

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

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