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Low levels of cell-free circulating miR-361-3p and miR-625* as blood-based markers for discriminating malignant from benign lung tumors.

Roth C, Stückrath I, Pantel K, Izbicki JR, Tachezy M, Schwarzenbach H - PLoS ONE (2012)

Bottom Line: Microarray profiling showed that miR-361-3p and miR-625* were significantly down-regulated in serum of lung cancer patients.Moreover, the levels of miR-625* were significantly lower in patients with large cell lung cancer (LCLC, p = 0.014) and smoking patients (p = 0.030) than in patients with adenocarcinoma and non-smoking patients, respectively.A rise in the levels of both miRs was observed in the postoperative samples compared with the preoperative levels (p = 0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT
The high mortality rate of lung cancer patients is mainly due to the late stage at which lung cancer is diagnosed. For effective cancer prevention programs and early diagnosis, better blood-based markers are needed. Hence, blood-based microarray profiling of microRNA (miR) expression was performed in preoperative serum of 21 non-small cell lung cancer (NSCLC) patients and 11 healthy individuals by microfluid biochips containing 1158 different miRs. Two out of the 30 most dysregulated miRs were further validated in serum of 97 NSCLC patients, 20 patients with benign lung diseases and 30 healthy individuals by TaqMan MicroRNA Assays. Microarray profiling showed that miR-361-3p and miR-625* were significantly down-regulated in serum of lung cancer patients. Their further evaluation by quantitative RT-PCR showed that the levels of miR-361-3p and miR-625* were lower in NSCLC than in benign disease (p = 0.0001) and healthy individuals (p = 0.0001, p = 0.0005, respectively). Moreover, the levels of miR-625* were significantly lower in patients with large cell lung cancer (LCLC, p = 0.014) and smoking patients (p = 0.030) than in patients with adenocarcinoma and non-smoking patients, respectively. A rise in the levels of both miRs was observed in the postoperative samples compared with the preoperative levels (p = 0.0001). Functional analyses showed that Smad2 and TGFß1 are not dysregulated by miR-361-3p and miR-625* in the lung cell line A549, respectively. Our present pilot study suggests that miR-361-3p and miR-625* might have a protective influence on the development of NSCLC, and the quantitative assessment of these miRs in blood serum might have diagnostic potential to detect NSCLC, in particular in smokers.

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Correlation of serum levels of miR-625* with the histological type of carcinoma and smoking behavior.The box plots show the different, relative amounts of miR-625* in healthy controls with unknown smoking behavior (H, n = 30) and all NSCLC patients with ADC (n = 39), SQCLC (n = 35), LCLC (n = 12), and non-smoking (NS, n = 7) and smoking (S, n = 28) behavior (A), in smoking NSCLC patients (S, n = 28) with ADC (n = 12), SQCLC (n = 10) and LCLC (n = 6) (B), and in healthy controls (H, n = 30), NS (n = 7) and S (n = 28) with malignant lung tumors (mal.), NS (n = 9) and S (n = 11) with benign lung tumors (ben.), NS (n = 16) and S (n = 39) with malignant or benign lung tumors (mal.+ben.) (C). As determined by Mann and Whitney-U test, the significant p values of the statistical evaluations of serum RNA and miR levels are indicated above the blots.
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pone-0038248-g004: Correlation of serum levels of miR-625* with the histological type of carcinoma and smoking behavior.The box plots show the different, relative amounts of miR-625* in healthy controls with unknown smoking behavior (H, n = 30) and all NSCLC patients with ADC (n = 39), SQCLC (n = 35), LCLC (n = 12), and non-smoking (NS, n = 7) and smoking (S, n = 28) behavior (A), in smoking NSCLC patients (S, n = 28) with ADC (n = 12), SQCLC (n = 10) and LCLC (n = 6) (B), and in healthy controls (H, n = 30), NS (n = 7) and S (n = 28) with malignant lung tumors (mal.), NS (n = 9) and S (n = 11) with benign lung tumors (ben.), NS (n = 16) and S (n = 39) with malignant or benign lung tumors (mal.+ben.) (C). As determined by Mann and Whitney-U test, the significant p values of the statistical evaluations of serum RNA and miR levels are indicated above the blots.

Mentions: Fig. 4A shows the prevalence of serum values of miR-625* in NSCLC patients with the different histological types, as well as in non-smoking and smoking NSCLC patients, whereas Fig. 4B only shows this prevalence in smoking NSCLC patients. As depicted in Fig. 4A, LCLC patients (p = 0.014) and smoking patients (p = 0.030) had significantly lower serum levels of miR-625* than ADC patients and non-smoking patients, respectively. Within the group of smoking patients, the LCLC patients had lower serum values of miR-625* (p = 0.001) compared to ADC patients (Fig. 4B). In the cohort of the patients with benign lung tumors the smoking patients also had lower levels of miR-625* than the non-smoking patients, but this difference was not significant (p = 0.080). However, when we merged both cohorts of NSCLC patients and patients with benign lung disease, we detected more significantly lower serum levels of miR-625* in smoking patients (p = 0.002) than non-smoking patients (Fig. 4C). Regrettably, the smoking behavior of healthy individuals was unknown to consider the relationship of the levels of miR-625* with the smoker status of healthy individuals.


Low levels of cell-free circulating miR-361-3p and miR-625* as blood-based markers for discriminating malignant from benign lung tumors.

Roth C, Stückrath I, Pantel K, Izbicki JR, Tachezy M, Schwarzenbach H - PLoS ONE (2012)

Correlation of serum levels of miR-625* with the histological type of carcinoma and smoking behavior.The box plots show the different, relative amounts of miR-625* in healthy controls with unknown smoking behavior (H, n = 30) and all NSCLC patients with ADC (n = 39), SQCLC (n = 35), LCLC (n = 12), and non-smoking (NS, n = 7) and smoking (S, n = 28) behavior (A), in smoking NSCLC patients (S, n = 28) with ADC (n = 12), SQCLC (n = 10) and LCLC (n = 6) (B), and in healthy controls (H, n = 30), NS (n = 7) and S (n = 28) with malignant lung tumors (mal.), NS (n = 9) and S (n = 11) with benign lung tumors (ben.), NS (n = 16) and S (n = 39) with malignant or benign lung tumors (mal.+ben.) (C). As determined by Mann and Whitney-U test, the significant p values of the statistical evaluations of serum RNA and miR levels are indicated above the blots.
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Related In: Results  -  Collection

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pone-0038248-g004: Correlation of serum levels of miR-625* with the histological type of carcinoma and smoking behavior.The box plots show the different, relative amounts of miR-625* in healthy controls with unknown smoking behavior (H, n = 30) and all NSCLC patients with ADC (n = 39), SQCLC (n = 35), LCLC (n = 12), and non-smoking (NS, n = 7) and smoking (S, n = 28) behavior (A), in smoking NSCLC patients (S, n = 28) with ADC (n = 12), SQCLC (n = 10) and LCLC (n = 6) (B), and in healthy controls (H, n = 30), NS (n = 7) and S (n = 28) with malignant lung tumors (mal.), NS (n = 9) and S (n = 11) with benign lung tumors (ben.), NS (n = 16) and S (n = 39) with malignant or benign lung tumors (mal.+ben.) (C). As determined by Mann and Whitney-U test, the significant p values of the statistical evaluations of serum RNA and miR levels are indicated above the blots.
Mentions: Fig. 4A shows the prevalence of serum values of miR-625* in NSCLC patients with the different histological types, as well as in non-smoking and smoking NSCLC patients, whereas Fig. 4B only shows this prevalence in smoking NSCLC patients. As depicted in Fig. 4A, LCLC patients (p = 0.014) and smoking patients (p = 0.030) had significantly lower serum levels of miR-625* than ADC patients and non-smoking patients, respectively. Within the group of smoking patients, the LCLC patients had lower serum values of miR-625* (p = 0.001) compared to ADC patients (Fig. 4B). In the cohort of the patients with benign lung tumors the smoking patients also had lower levels of miR-625* than the non-smoking patients, but this difference was not significant (p = 0.080). However, when we merged both cohorts of NSCLC patients and patients with benign lung disease, we detected more significantly lower serum levels of miR-625* in smoking patients (p = 0.002) than non-smoking patients (Fig. 4C). Regrettably, the smoking behavior of healthy individuals was unknown to consider the relationship of the levels of miR-625* with the smoker status of healthy individuals.

Bottom Line: Microarray profiling showed that miR-361-3p and miR-625* were significantly down-regulated in serum of lung cancer patients.Moreover, the levels of miR-625* were significantly lower in patients with large cell lung cancer (LCLC, p = 0.014) and smoking patients (p = 0.030) than in patients with adenocarcinoma and non-smoking patients, respectively.A rise in the levels of both miRs was observed in the postoperative samples compared with the preoperative levels (p = 0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

ABSTRACT
The high mortality rate of lung cancer patients is mainly due to the late stage at which lung cancer is diagnosed. For effective cancer prevention programs and early diagnosis, better blood-based markers are needed. Hence, blood-based microarray profiling of microRNA (miR) expression was performed in preoperative serum of 21 non-small cell lung cancer (NSCLC) patients and 11 healthy individuals by microfluid biochips containing 1158 different miRs. Two out of the 30 most dysregulated miRs were further validated in serum of 97 NSCLC patients, 20 patients with benign lung diseases and 30 healthy individuals by TaqMan MicroRNA Assays. Microarray profiling showed that miR-361-3p and miR-625* were significantly down-regulated in serum of lung cancer patients. Their further evaluation by quantitative RT-PCR showed that the levels of miR-361-3p and miR-625* were lower in NSCLC than in benign disease (p = 0.0001) and healthy individuals (p = 0.0001, p = 0.0005, respectively). Moreover, the levels of miR-625* were significantly lower in patients with large cell lung cancer (LCLC, p = 0.014) and smoking patients (p = 0.030) than in patients with adenocarcinoma and non-smoking patients, respectively. A rise in the levels of both miRs was observed in the postoperative samples compared with the preoperative levels (p = 0.0001). Functional analyses showed that Smad2 and TGFß1 are not dysregulated by miR-361-3p and miR-625* in the lung cell line A549, respectively. Our present pilot study suggests that miR-361-3p and miR-625* might have a protective influence on the development of NSCLC, and the quantitative assessment of these miRs in blood serum might have diagnostic potential to detect NSCLC, in particular in smokers.

Show MeSH
Related in: MedlinePlus