Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness

Hou, Pei-Chi; Li, Yo Hua; Lin, Shih Chieh; Lin, Shau Chieh; Lee, Jenq Chang; Lin, Bo; Liou, Jing Ping; Chang, Jang Yang; Kuo, Ching Chuan; Liu, Yi Min; Sun, Han; Tsai, Shaw-Jenq

doi:10.1158/0008-5472.can-16-2990

Cited by 57 publications

(45 citation statements)

References 32 publications

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“…d ). Our previous data showed that caspase‐3 could mediate the production of prostaglandin E 2 (PGE 2 ), a growth regulator that increases tumor growth in many types of cancers, including colon cancer . To determine if CASP3KO caused difference in PGE 2 production, we measured PGE 2 levels in supernatants from control and irradiated HCT116 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous data 4,16 showed that caspase-3 could mediate the production of prostaglandin E 2 (PGE 2 ), a growth regulator that increases tumor growth in many types of cancers, including colon cancer. [17][18][19] To determine if CASP3KO caused difference in PGE 2 production, we measured PGE 2 levels in supernatants from control and irradiated HCT116 cells. Our results indicate the significantly reduced level of PGE 2 was found in HCT116 CASP3KO cells when compared to the control cells under both non-irradiated and irradiated conditions (Supporting Information Fig.…”

Section: Increased Sensitivities To Radiotherapy and Chemotherapy In mentioning

confidence: 99%

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Caspase‐3 regulates the migration, invasion and metastasis of colon cancer cells

Zhou

Liu

et al. 2018

Intl Journal of Cancer

183

109

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Caspase-3 (CASP3) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy or immunotherapy. It is often used as a marker for efficacy of cancer therapy. However, recent reports indicate that caspase-3 has also non-apoptotic roles such as promotion of tumor relapse and tumor angiogenesis. Therefore, the roles of caspase-3 in tumor progression remain to be defined clearly. In our study, we established caspase-3 knockout (KO) colon cancer cell lines by use of the CRISPR technology. In vitro, caspase-3 knockout HCT116 cells were significantly less clonogenic in soft agar assays. They were also significantly less invasive and more sensitive to radiation and mitomycin C than control cells. In vivo, CASP3KO cells formed tumors at rates similar to control cells but were significantly more sensitive to radiotherapy. They were also less prone to pulmonary metastasis when inoculated either subcutaneously or intravenously. At the mechanistic level, caspase-3 gene knockout appeared to cause reduced EMT phenotypes when compared to parental HCT116 cells. Indeed, they showed significantly increased E-cadherin expression, reduced N-cadherin, Snail, Slug and ZEB1 expression than control cells. Therefore, therapeutic targeting of caspase-3 may not only increase the sensitivity of cancer cell to chemotherapy and radiotherapy, but also inhibit cancer cell invasion and metastasis.

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Section: Resultsmentioning

confidence: 99%

Section: Increased Sensitivities To Radiotherapy and Chemotherapy In mentioning

confidence: 99%

Caspase‐3 regulates the migration, invasion and metastasis of colon cancer cells

Zhou

Liu

et al. 2018

Intl Journal of Cancer

183

109

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“…DUSP2-It has been shown that DUSP2 is involved in P53-induced cell apoptosis; however, this phosphatase is dramatically reduced in different solid tumors compared to their normal counterparts. Accordingly, it was reported that the diminished DUSP2 leads to prolonged ERK phosphorylation, increased drug resistance, as well as an inflammatory response due to overproduction of prostaglandin in colorectal cancer [106]. It was also reported that DUSP2 knockdown in xenograft tumors promotes higher vessel density and metastasis events from colorectal cancer to the liver [107].…”

Section: Ptps That Act As Tumor Suppressorsmentioning

confidence: 99%

Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?

Ferreira-Halder¹,

Clerici²,

Faria³

et al. 2020

Tumor Progression and Metastasis

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Reversible phosphorylation of proteins, executed by kinases and phosphatases, is the major posttranslational protein modification in eukaryotic cells, causing them to become activated or deactivated. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a broad number of diseases, including cancer. Few decades ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors. However, nowadays, accumulating evidence demonstrates that a misregulation of PTP activities plays a crucial and decisive role in cancer progression and metastasis. In this chapter, we will focus on the molecular aspects that support the crucial role of PTPs in cancer and in turn make them promising for prediction, monitoring, and rational appropriate therapy selection of individual patients.

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“…For drug experiment, mice were randomly assigned to experimental or control groups after two weeks of inoculation. In the treatment group, mice received vehicle or B390 (12.5 mg/kg) by oral gavage with exible feeding tubes, ve days/week for two consecutive weeks (8). Mice were sacri ced three days after the last treatment and tumors were excised.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Due to the di culty in restoration of a tumor suppressor protein in reality, we aimed to identify molecules which may exert similar functions. By cross-referencing our previously published microarray dataset (8) with connectivity map 14, we identi ed a list of inhibitors that function like DUSP2 (Fig. 3A).…”

Section: Restoration Of Dusp2-mediated Functions By Novel Histone Deamentioning

confidence: 99%

A novel HDAC inhibitor suppresses extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination

Huang

et al. 2020

Preprint

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Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Loss-of-function of dual specificity phosphatase 2 (DUSP2), a critical regulator of MAPKs signaling, is highly associated with cancer malignancies. Therefore, it may provide new therapeutic strategy if the actions of DUSP2 can be restored. Methods The tumor suppressor role of DUSP2 was demonstrated via DUSP2 re-expression in the orthotopic mouse model of pancreatic cancer and knockout of Dusp2 in the pancreas by transgenic mouse model. Immunohistochemical staining and histology analysis was performed to evaluate tumor development and progression. Bioinformatic analysis was utilized to identify potential drug which mimics DUSP2 re-expression. Pancreatic cancer cell survival, migration ability, and the expression and function of extracellular vesicle (EV) associated vascular endothelial growth factor C (VEGF-C) was measured. The effect of the novel HDAC inhibitor on pancreatic cancer progression was evalulated by orthotopic mouse model. Results Forced expression of DUSP2 abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC formation. Increased HDAC1 expression was found in PDAC and inhibition of HDAC showed similar gene profile as Kras knockdown and DUSP2 re-expression. Treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased EV-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Conclusions Our data provide the proof-of-concept evidence to demonstrate the potential of using novel HDAC inhibitor in PDAC treatment which alleviates loss-of-DUSP2-mediated pathological processes.

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Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon Cancer Stemness

Cited by 57 publications

References 32 publications

Caspase‐3 regulates the migration, invasion and metastasis of colon cancer cells

Caspase‐3 regulates the migration, invasion and metastasis of colon cancer cells

Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?

A novel HDAC inhibitor suppresses extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination

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