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

Takeshita, Michinori; Koga, Tomohiro; Takayama, K.; Kouso, Hidenori; Nishimura-Ikeda, Yuko; Yoshino, Ichiro; Maehara, Yoshihiko; Nakanishi, Yoichi; Sueishi, Katsuo

doi:10.1002/ijc.23673

Cited by 19 publications

(28 citation statements)

References 44 publications

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“…In contrast, we demonstrated that reduced CHFR protein expression is associated with squamous cell carcinoma of NSCLC, smoking habit and tumor differentiation. 22 In the present study, we showed that EGFR gene mutation of clinical NSCLC samples was significantly related to resistance to PTX in opposition to CHFR methylation. In opposition to our results, a recent clinical study showed that the response rate of paclitaxel plus carboplatin treatment in the EGFR mutation-positive subgroup is higher than that in the EGFR wild-type subgroup.…”

Section: Discussionmentioning

confidence: 49%

“…Sodium bisulfite conversion of genomic DNA was performed using the EZ DNA Methylation Kit (Zymo Research, Orange, CA), as described previously. 22,31 Methylation-specific PCR (MSP) was carried out with the following oligonucleotide primers, which were designed to be specific to either the methylated or unmethylated DNA sequence of the CHFR gene after sodium bisulfite conversion as described above. The methylated DNA-specific primers were MF (5'-ATA TAA TAT GGC GTC GAT C-3') and MR (5'-TCA ACT AAT CCG CGA AAC G-3').…”

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confidence: 99%

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Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer

Takeshita¹,

Koga²,

Takayama³

et al. 2010

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 49%

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confidence: 99%

Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer

Takeshita¹,

Koga²,

Takayama³

et al. 2010

Cancer Biology & Therapy

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“…In contrast to the study of Tang et al (30), the prognostic significance of AURKA expression in the present study appears to hold true for both histological subtypes. There is a lack of consensus on this issue, with previous studies debating on the prognostic significance of AURKA in SqCCL (17,18). Furthermore, perimembrane immunohistochemical staining was demonstrated to be a marked predictor of poor prognosis in patients with SqCCL, but not in patients with AdC (16), whereas microarray data analysis demonstrated that AURKA mRNA overexpression is associated with poor prognosis in patients with AdC, but not in patients with SqCCL (30).…”

Section: Discussionmentioning

confidence: 99%

“…AURKA serves a central role in recruiting other mitotic spindle members (5). A number of previous studies conducted in lung cancer have investigated the prognostic value of various of the aforementioned genes, including TPX2 (15), AURKA (16)(17)(18) and AURKB (18)(19)(20)(21); however, the prognostic value of AURKA and AURKB remains a matter of debate. No information on the potential prognostic significance in human NSCLC has yet been provided for DLGAP5, CKAP5 or TTK.…”

Section: Introductionmentioning

confidence: 99%

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

et al. 2017

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Abstract. Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large-associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and β-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non-small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P= 0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P= 0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24-7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors.

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“…7 CHFR is a ubiquitin ligase of Plk1 and Aurora-A. It functions as a mitotic checkpoint by delaying entry into metaphase in response to mitotic stress induced by nocodazole or paclitaxel.…”

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

Cited by 19 publications

References 44 publications

Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer

Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non-small-cell lung cancer

AURKA mRNA expression is an independent predictor of poor prognosis in patients with 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

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