Reduced expression of cell-cycle regulator p27Kip1 correlates with a shortened survival in non-small cell lung cancer

Tsukamoto, Shuntaro; Sugio, Kenji; Sakada, Takashi; Ushijima, Chie; Yamazaki, Koji; Sugimachi, Keizō

doi:10.1016/s0169-5002(01)00216-1

Cited by 46 publications

(29 citation statements)

References 26 publications

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“…Alterations of many cell-cycle checkpoint proteins, including the INK4 family (p16) and the Cip/Kip family (p21, p27 and p57), have been reported to predict prognosis in NSCLC, [34][35][36][37] but this is the first study to report CHFR methylation as an independent risk factor for recurrence rate and prognosis in NSCLC. As described above, the reason for this may involve the positive relationship between CHFR methylation and several risk factors for patient survival, but the overall mechanisms underlying the potential for CHFR to influence the recurrence rates or prognoses of patients with malignant tumors remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

Koga

Takeshita

Yano

et al. 2010

Intl Journal of Cancer

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Aberrant promoter methylation of the checkpoint gene with forkhead-associated domain and ring finger (CHFR) gene is frequently detected in human cancer. We previously demonstrated that diminished CHFR expression was significantly correlated with both poor prognosis and heavy smoking in nonsmall cell lung cancer (NSCLC). Conversely, epidermal growth receptor (EGFR) mutation is detected in NSCLC among those who have never smoked or smoked lightly. To address the frequency of CHFR hypermethylation as well as differences in the distributions and clinicopathologic backgrounds against EGFR mutation in NSCLC, we investigated a large group of 208 NSCLC patients, including 165 with adenocarcinoma (ADC), 40 with squamous cell carcinoma and three others. We found that CHFR hypermethylation and EGFR mutation are mutually exclusive and have contrastive clinicopathologic backgrounds in NSCLC. Methylation-specific polymerase chain reaction (MSP) and direct DNA sequencing were performed to detect CHFR hypermethylation and EGFR mutation, respectively. CHFR hypermethylation was found in 29 cases (14%) (16 ADC (8%), 12 SCC (6%) and one adenosquamous carcinoma), while EGFR mutation was detected in 48 (23%) cases, all of which were ADC. CHFR hypermethylation and EGFR mutation were mutually exclusive (p 5 0.004). NSCLC with altered CHFR was significantly correlated with smoking history, poor differentiation, lymphatic invasion, and poor prognosis; this contrasted sharply with EGFR mutation, which had statistically better clinical outcomes. Our results demonstrate that CHFR loss might be critical for the tumorigenesis of NSCLC in patients with a history of smoking and induces tumors of a more malignant phenotype than the EGFR mutation. Thus, CHFR alteration should be considered a therapeutic target against NSCLC in patients with poor prognoses.Lung cancer is a leading cause of cancer mortality worldwide; it accounts for over a million deaths annually and still has a poor prognosis.1 Nonsmall cell lung cancer (NSCLC) is the main form of lung cancer, which has three major histologic types: squamous cell carcinoma (SCC), adenocarcinoma (ADC) and large cell carcinoma (LCC).2 Among these, ADC has become the most common type in Western countries.2 It is widely accepted that NSCLC is the result of a series of molecular changes, including oncogene activation and the loss of tumor suppressor genes. Recently, epidermal growth receptor (EGFR) mutation has been receiving increasing attention for its specific clinical response to the anticancer drug gefitinib.3 EGFR mutations are found in 10-40% of NSCLC and are clinicopathologically characterized by female gender, no smoking history and ADC histology, especially with bronchioloalveolar features. [4][5][6] In addition to these data, patients with EGFR mutation have fairly good survival rates. 3Plenty of knowledge has accumulated about EGFR mutation, but there is still no full understanding of the molecular abnormality that is a counterpart of NSCLC and that is associated with smoking and poor clin...

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Section: Discussionmentioning

confidence: 99%

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

Koga

Takeshita

Yano

et al. 2010

Intl Journal of Cancer

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“…So far, the loss of expression of a G1-S phase cell cycle checkpoint protein, such as the INK4 family (p16) and the Cip/Kip family (p21, p27 and p57), has been reported to predict poor prognosis in NSCLC, although not all studies have reached statistical significance. [39][40][41][42] This is the first study to report that an early M-phase cell cycle checkpoint protein, CHFR, is an independent and significant prognostic factor in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

Takeshita

Koga

Takayama

et al. 2008

Intl Journal of Cancer

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Loss of tumor suppressors and activation of oncogenes lead to carcinogenesis. Abnormal expression of CHFR, a novel checkpoint gene, or of Aurora kinases, key regulators of mitosis, has been detected in a variety of solid tumors. Recently, CHFR has been revealed to ensure chromosomal stability by controlling the expression level of Aurora-A in vitro. However, the frequency of aberrant expression of these proteins and the association with clinicopathologic parameters remain poorly defined in nonsmall-cell lung cancer (NSCLC). In this study, we investigated the immunohistochemical protein expression of CHFR and Aurora-A in 157 NSCLC cases and evaluated the association between clinicopathologic parameters statistically. The relationship between CHFR protein and mRNA levels and the association between this relationship and promoter methylation of the CHFR gene were also examined in 20 frozen sections of NSCLC. Overexpression of Aurora-A and reduced expression of CHFR were found in 94 cases (59.8%) and 62 cases (39%) of NSCLC, respectively, and those were significantly correlated with tumor differentiation and size. Moreover, diminished CHFR expression was significantly associated with smoking-related squamous cell carcinoma cases and poor prognosis. Multivariate analysis revealed that CHFR expression was an independent prognostic factor. A statistical correlation was evident between CHFR protein and mRNA expression. In conclusion, our results suggest the aberrant expression of Aurora-A and/or of CHFR contributed to the increase in the malignant potential of NSCLC. We also revealed that CHFR expression was predominantly impaired in smoking-related squamous cell carcinoma and might be a useful prognostic marker in NSCLC.

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“…56 Downregulation of p27 KIP1 associates with a poor outcome in NSCLC patients and is a significant prognostic factor in multivariate analyses. [58][59][60][61] In contrast, SCLC exhibit increased p27 KIP1 expression when compared to the normal lung epithelium. 61 Together, these data suggest that p27 KIP1 might play distinct biological roles in the pathogenesis of SCLC and NSCLC.…”

Section: Ink4amentioning

confidence: 99%

Role of cell cycle regulators in lung carcinogenesis

Eymin

Gazzéri

2010

Cell Adhesion & Migration

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Reduced expression of cell-cycle regulator p27Kip1 correlates with a shortened survival in non-small cell lung cancer

Cited by 46 publications

References 26 publications

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non‐small cell lung cancer

CHFR expression is preferentially impaired in smoking‐related squamous cell carcinoma of the lung, and the diminished expression significantly harms outcomes

Role of cell cycle regulators in lung carcinogenesis

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