High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients

Magnussen, Gry Irene; Hellesylt, Ellen; Nesland, Jahn M.; Tropé, Claes G.; Flørenes, Viví Ann; Holm, Ruth

doi:10.1186/1471-2407-13-288

Cited by 36 publications

(42 citation statements)

References 31 publications

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“…Notably, WEE1 mRNA expression was significantly increased in CRC tissues compared with the corresponding adjacent normal tissues and the upregulation of WEE1 mRNA was observed in 41.9% of patients with CRC (18/43 cases). The upregulation of WEE1 mRNA in CRC is not only in agreement with the expression pattern of WEE1 in other human malignancy tissues, including HCC (16)(17)(18)(19), but also suggests WEE1 upregulation as a common event during the carcinogenesis of human malignancies, including CRC.…”

Section: Discussionsupporting

confidence: 77%

“…As previously described in melanoma and vulvar squamous cell carcinoma (17,18), immunohistochemical staining of WEE1 was predominantly detected in the cellular nucleus despite evidence of positive staining being identified in the cytoplasm. Positive WEE1 expression ( Fig.…”

Section: Resultssupporting

confidence: 71%

“…Although the upregulation of WEE1 has been observed in several human malignancies, including in HCC and melanoma, and in numerous types of tumor cell lines including glioblastoma and breast cancer (16)(17)(18)(19), the data regarding the expression pattern of WEE1 in human CRC remains limited. Using a cDNA array and semi-quantitative RT-PCR, Backert et al (26) identified that WEE1 expression was decreased in human colon cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact role of WEE1 in human malignancy still needs further studies in order to be understood, Magnussen et al (18) previously identified that high WEE1 expression is associated with lymph node metastasis and poor differentiation of vulvar squamous cell carcinoma. The present study therefore correlated WEE1 mRNA upregulation with clinicopathological characteristics of CRC and revealed that the upregulation of WEE1 mRNA was significantly correlated with the distant metastasis of CRC.…”

Section: Upregulation Of Wee1 Mrna ----------------------------------mentioning

confidence: 99%

“…WEE1 is therefore a critical G2 checkpoint regulator that induces interphase and prevents the initiation of mitosis (15). Previous studies have shown that WEE1 expression is increased in various types of human malignancies including melanoma and vulvar squamous cell, ovarian and hepatocellular carcinoma (HCC) (16)(17)(18)(19). Elevated WEE1 expression is also documented in glioblastoma and breast cancer cells, and the inhibition of WEE1 in these cells results in suppressed cellular proliferation and increased apoptosis (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer

et al. 2017

Oncology Letters

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Abstract. WEE1 is a serine/threonine protein kinase that inactivates cell division cycle 2 and is therefore a critical cell cycle regulator. Increased WEE1 expression has been observed in numerous types of human malignancies, including hepatocellular carcinoma and melanoma. WEE1 inhibition also results in evident anti-tumor effects in several human tumor cells including colon cancer cells, suggesting WEE1 as a potential therapeutic target for the treatment of cancer. However, the expression pattern of WEE1 in colorectal cancer (CRC) remains unclear. In the present study, WEE1 mRNA expression in 43 cases of CRC tissues matched with adjacent normal tissues was determined by reverse-transcription quantitative polymerase chain reaction. The results demonstrated that WEE1 mRNA expression was significantly increased in CRC tissues and that this upregulation correlated significantly with hepatic metastasis, distant metastasis and high tumor node metastasis (TNM) stage of CRC. Additionally, WEE1 protein in 102 CRC tissue samples was detected by immunohistochemistry, and positive staining of WEE1 was identified in more than half of patients with CRC. WEE1 staining scores were also observed to be associated with distant metastasis and high TNM stage of CRC. In addition, patients with CRC with high WEE1 staining score (2+ or 3+) exhibited either poorer overall survival or poorer disease-free survival compared with those with low WEE1 staining score (0 or 1+). The multivariable Cox model also identified a high WEE1 staining score as well as high TNM stage to be independent prognostic factors for CRC. In conclusion, WEE1 upregulation is associated with a high degree of malignancy and poor prognosis of CRC, suggesting WEE1 as a potential prognostic biomarker for CRC.

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Section: Discussionsupporting

confidence: 77%

Section: Resultssupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Upregulation Of Wee1 Mrna ----------------------------------mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer

et al. 2017

Oncology Letters

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Development of Potent Pyrazolopyrimidinone‐Based WEE1 Inhibitors with Limited Single‐Agent Cytotoxicity for Cancer Therapy

2018

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WEE1 kinase regulates the G /M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.

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Synthetic retinoid CD437 induces apoptosis and acts synergistically with TRAIL receptor-2 agonist in malignant melanoma

Magnussen

Rosnes

Shahzidi

et al. 2012

Biochemical and Biophysical Research Communications

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Background: Malignant melanoma has an increasing incidence rate and the metastatic disease is notoriously resistant to standard chemotherapy. Loss of cell cycle checkpoints is frequently found in many cancer types and makes the cells reliant on compensatory mechanisms to control progression. This feature may be exploited in therapy, and kinases involved in checkpoint regulation, such as Wee1 and Chk1/2, have thus become attractive therapeutic targets. Methods: In the present study we combined a Wee1 inhibitor (MK1775) with Chk1/2 inhibitor (AZD7762) in malignant melanoma cell lines grown in vitro (2D and 3D cultures) and in xenografts models. Results: Our in vitro studies showed that combined inhibition of Wee1 and Chk1/2 synergistically decreased viability and increased apoptosis (cleavage of caspase 3 and PARP), which may be explained by accumulation of DNA-damage (increased expression of γ-H2A.X)-and premature mitosis of S-phase cells. Compared to either inhibitor used as single agents, combined treatment reduced spheroid growth and led to greater tumour growth inhibition in melanoma xenografts. Conclusions: These data provide a rationale for further evaluation of the combination of Wee1 and Chk1/2 inhibitors in malignant melanoma.

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High expression of wee1 is associated with malignancy in vulvar squamous cell carcinoma patients

Cited by 36 publications

References 31 publications

Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer

Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer

Development of Potent Pyrazolopyrimidinone‐Based WEE1 Inhibitors with Limited Single‐Agent Cytotoxicity for Cancer Therapy

Synthetic retinoid CD437 induces apoptosis and acts synergistically with TRAIL receptor-2 agonist in malignant melanoma

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