p12CDK2-AP1 inhibits breast cancer cell proliferation and in vivo tumor growth

Zhou, Wei‐Fang; Guan, Xiaoyan; Wang, Longyun; Liao, Yuping; Huang, Juan

doi:10.1007/s00432-012-1286-z

Cited by 17 publications

(11 citation statements)

References 18 publications

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“…Our observations are in accordance with a wealth of laboratory studies supporting the notion that CDK2AP1 behaves as a tumour-suppressor gene in a variety of tumours (12)(13)(14)(15)(16)(17)(18)(19). Zou et al reported that CDK2AP1 inhibited the proliferation of breast cancer cells and the in vivo growth of tumour cells (15).…”

Section: Discussionsupporting

confidence: 91%

mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters

Gera

Mokbel

Jiang

et al. 2018

Cancer Genomics Proteomics

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Background: Cyclin-dependent kinase 2associated protein 1 (CDK2AP1) interacts with CDK2AP2, modulates the actions of transforming growth factor-B1, cyclin-dependent kinase 2 and retinoblastoma protein, and closely interacts with micro-RNA21 and micro-RNA25. Our objective was to determine if CDK2AP1 mRNA expression levels were consistent with tumour-suppressive functions in breast cancer. Materials and Methods: A total of 134 samples were analysed. CDK2AP1 mRNA levels were measured using quantitative polymerase chain reaction (RT-PCR) and normalised against glyceraldehyde 3-phosphate dehydrogenase mRNA. Levels in breast cancer and adjacent non-cancerous breast tissue were analysed against pathological and clinical parameters (TNM staging, survival over a 10-year follow-up period). Results: Normalised CDK2AP1 expression was 38-fold higher in adjacent noncancerous breast tissue than in breast cancer. CDK2AP1 expression in disease-free patients at 10 years was more than threefold that of patients who died of breast cancer. However, neither of these differences in expression levels reached statistical significance. CDK2AP1 mRNA levels were higher in TNM1 compared to TNM3 (p=0.016) and with TNM4 (p=0.016). There were no significant associations between CDK2AP1 expression and estrogen receptor status, tumour grade and tumour type. There was no significant difference in overall survival between patients with high and those with low CDK2AP1 mRNA levels after a median follow-up of 10 years (Kaplan-Meier analysis, p=0.872). Conclusion: To our knowledge, this is the first study in the literature to examine the mRNA expression of CDK2AP1 in human breast cancer over a long-term follow-up period. A compelling relationship exists between high CDK2AP1 mRNA expression and lower TNM classification of breast cancer, which is consistent with CDK2AP1 having a tumoursuppressive function. Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is hypothesised to be a tumour suppressor which works through the mediation of several other genes and proteins. First discovered in 1995 as 'deleted in oral cancer-1' (DOC1) gene (1), investigators have since found evidence for its growth-/tumour-suppressive action and confirmed it to be likely implicated in the development of many cancer types (2, 3). CDK2AP1 and its associated homolog CDK2AP2 likely work together to effectively suppress cell growth due to their probable structural and functional relation (4); CDK2AP2 is a known tumour suppressor (5) which we previously investigated and provided evidence for its tumour-suppressive function in human breast cancer. The interaction between the two was recorded by using CDK2AP1 as 'bait' in liver cDNA screening and was verified both in vitro and in cells (6). Multiple investigations have been conducted regarding the relationship between different micro-RNAs (miRs) and CDK2AP1. Using cells taken from the tumour-free surgical margins of 18 patients with head and neck squamous cell carcinomas, miR-21 was found to be inversely correlated with CDK2AP1 a...

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Section: Discussionsupporting

confidence: 91%

mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters

Gera

Mokbel

Jiang

et al. 2018

Cancer Genomics Proteomics

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“…Recently, several studies have reported negative or decreased DOC‐1 expression in gastric cancer tissue, and this was highly correlated with more advanced tumor stage and invasion [], risk of lymph node metastases, and decreased survival in patients with OSCC []. Similar reports were observed from many cancer types including prostate cancer [], esophageal carcinoma [], breast cancer [], colorectal cancer [], and lung cancer [].…”

Section: Introductionsupporting

confidence: 83%

Association of oral tumor suppressor gene deleted in oral cancer‐1 (DOC‐1) in progression of oral precancer to cancer

Katarkar

Patel

Mukherjee

et al. 2014

Oral Science International

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a b s t r a c tIntroduction: Deleted in oral cancer-1 (DOC-1), a highly conserved tumor suppressor gene, encodes a specific cyclin-dependent kinase 2-associated protein 1 (p12 DOC-1 ). The protein DOC-1 arrests the cells in the G 1 phase of the cell cycle and regulates DNA replication in the S phase of the cell cycle. It is known that DOC-1 is downregulated in head and neck cancer. Hence, the aim of the study was to analyze the messenger RNA (mRNA) expressions of DOC-1 in patients with oral lichen planus (OLP), leukoplakia (LPK), oral submucous fibrosis (OSF), and oral squamous cell carcinoma (OSCC) in comparison to normal control subjects, and these were correlated with differential oral habits and duration of exposure. Materials and methods: Semiquantitative one-step reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the potential role of DOC-1 in differential oral conditions. Results: The expression of DOC-1 at the transcriptional level was found to be consistently reduced (39.13%) or non-detectable (60.87%) in OSCC cases; LPK cases also showed reduced (26.19%) or non-detectable (59.52%) DOC-1 expression, and overexpression of DOC-1 was observed in patients with OSF (42.3%) and OLP (35.29%) as compared to the normal control groups. A marked reduction in DOC-1 expression was observed in patients who smoke bidi and chew tobacco compared to patients who smoke cigarettes and chew pan. An overall reduced expression of DOC-1 with an increase in the duration of exposure was observed.Conclusions: The overexpression of DOC-1 in oral premalignant disease groups with reduced or loss of expression in OSCC groups suggests its association in the progression of oral carcinogenesis, suggesting DOC-1 to be an important prognostic indicator for oral cancer.

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“…In spite of its important role in cancer suppression, work on CDK2-AP1 in breast cancer is insufficient. Only one single report had indicated that P12 can inhibit growth of breast cancer cells in vivo and in vitro by regulating the cell cycle [ 18 ]. However, either its role in cell behavior or chemotherapeutic sensitivity of breast cancer remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CDK2-AP1 inhibits growth of breast cancer cells by regulating cell cycle and increasing docetaxel sensitivity in vivo and in vitro

Xiang

Zong

et al. 2014

Cancer Cell Int

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BackgroundCell cycle regulatory pathway is a well-established pathway mainly dependent on cyclin-dependent kinases (CDKs), which are regulated positively by cyclins and negatively by cyclin-dependent kinase inhibitors(CKIs). Cyclin-dependent kinase 2 associate protein 1(CDK2-AP1) is a specific negative regulatory protein for CDK2, is important in the cancer cell cycle. However, the function of CDK2-AP1 in breast cancer remains unclear. We designed therefore explored the effects of CDK2-AP1 on breast cancer growth and its chemo-sensitivity.MethodsExpression of CDK2-AP1, CDK2 and CyclinD1 in 209 cases of pathological specimens using IHC staining was measured. Lost-of-function and Gain-of-function assays were used in vivo and in vitro relating to the specific role of CDK2-AP1 in breast cancer. We analyzed in vivo and in vitro the impact of CDK2-AP1 on chemotherapy sensitivity in breast cancer.ResultsThe positive ratio of CDK2-AP1 expression was reduced successively in normal breast tissue, DCIS, invasive breast cancer and relapsed breast cancer, however, with CDK2 and CyclinD1 it was suggested that CDK2-AP1 was correlated closely with the tumorigenesis and progress, and might work as a tumor suppressor. After down-regulating CDK2-AP1 in breast cancer cells, the cell cycle was accelerated and cell proliferation enhanced. The cell cycle was arrested in G0/G1 phase and G2/M phase after up-regulating CDK2-AP1 in breast cancer cells, inhibiting cell proliferation. The expression of CDK2 and CyclinD1 changed accordingly after downregulation or upregulation of CDK2-AP1 by western blot, suggesting a role of the CDK2-AP1/CDK2/CyclinD1 cell cycle pathway in the initiation and progression of breast cancer. Similar results were obtained in animal assays. The data indicates that CDK2-AP1 can induce sensitivity to docetaxel treatment in breast cancer cells.ConclusionsCDK2-AP1 affects tumorigenesis, tumor growth and chemo-sensitivity by cell cycle regulation, which can potentially to be a therapeutical agent in breast cancer.

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p12CDK2-AP1 inhibits breast cancer cell proliferation and in vivo tumor growth

Cited by 17 publications

References 18 publications

mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters

mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters

Association of oral tumor suppressor gene deleted in oral cancer‐1 (DOC‐1) in progression of oral precancer to cancer

CDK2-AP1 inhibits growth of breast cancer cells by regulating cell cycle and increasing docetaxel sensitivity in vivo and in vitro

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