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The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.

Qiu F, Yang L, Lu X, Chen J, Wu D, Wei Y, Nong Q, Zhang L, Fang W, Chen X, Ling X, Yang B, Zhang X, Zhou Y, Lu J - PLoS Genet. (2016)

Bottom Line: Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology.We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis.These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis.

View Article: PubMed Central - PubMed

Affiliation: The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China.

ABSTRACT
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70-4.01). These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32-1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.

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The effects of MKK7 p.Glu116Lys on tumor growth and metastasis.(A, B). Subcutaneously implanted MKK7-116Glu (A549-MKK7-116Glu and L78-MKK7-116Glu cells) and MKK7-116Lys (A549-MKK7-116Lys and L78-MKK7-116Lys cells) cells xenografted tumors were established and were observed for a total of 4 weeks. Tumor volumes represented the mean ± SD of 6 mice per group. Columns, mean; bars, SD. The symbol “★” indicated a statistical significance with P < 0.05 between the cells transfected with the two different transfectants. (C-E). A549-MKK7-116Glu or A549-MKK7-116Lys cells were separately injected into the tail vein of each mouse. After proximately 10 weeks, lung metastases were evaluated using magnetic resonance imaging, macroscopic observation and histomorphology under microscopy. The red loops and arrows indicate the metastases.
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pgen.1005955.g003: The effects of MKK7 p.Glu116Lys on tumor growth and metastasis.(A, B). Subcutaneously implanted MKK7-116Glu (A549-MKK7-116Glu and L78-MKK7-116Glu cells) and MKK7-116Lys (A549-MKK7-116Lys and L78-MKK7-116Lys cells) cells xenografted tumors were established and were observed for a total of 4 weeks. Tumor volumes represented the mean ± SD of 6 mice per group. Columns, mean; bars, SD. The symbol “★” indicated a statistical significance with P < 0.05 between the cells transfected with the two different transfectants. (C-E). A549-MKK7-116Glu or A549-MKK7-116Lys cells were separately injected into the tail vein of each mouse. After proximately 10 weeks, lung metastases were evaluated using magnetic resonance imaging, macroscopic observation and histomorphology under microscopy. The red loops and arrows indicate the metastases.

Mentions: To further determine the effect of p.Glu116Lys on tumor growth and metastasis in vivo, cells with stably over-expressing MKK7-116Glu or MKK7-116Lys were injected into nude mice subcutaneously (both for A549 and L78 cell lines), and intravenously (for A549 cell line only), respectively. As is shown in Fig 3A, the injection of MKK7-116Lys cells resulted in tumor formation began 4 days earlier compared to the results from injection of MKK7-116Glu cells. The tumor grew faster, and after 4 weeks, the tumor size in the former group was larger than the latter group (For A549: 1246.3±102.3 mm3vs. 846.3±78.5 mm3, P <0.001, Fig 3A; for L78: 1474.5±99.4 mm3vs. 921.1±88.4 mm3, P <0.001, Fig 3B). Moreover, we used the MRI and histology examination to determine whether the MKK7 p.Glu116Lys could cause tumor metastases, and found that all the mice injected with A549 cells over-expressing MKK7-116Lys suffered from pulmonary metastasis, while the mice group injected with MKK7-116Glu A549 cells did not (Fig 3C, 3D and 3E). These findings demonstrated that MKK7-116Lys variant enhanced lung tumor growth and metastasis in vivo.


The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.

Qiu F, Yang L, Lu X, Chen J, Wu D, Wei Y, Nong Q, Zhang L, Fang W, Chen X, Ling X, Yang B, Zhang X, Zhou Y, Lu J - PLoS Genet. (2016)

The effects of MKK7 p.Glu116Lys on tumor growth and metastasis.(A, B). Subcutaneously implanted MKK7-116Glu (A549-MKK7-116Glu and L78-MKK7-116Glu cells) and MKK7-116Lys (A549-MKK7-116Lys and L78-MKK7-116Lys cells) cells xenografted tumors were established and were observed for a total of 4 weeks. Tumor volumes represented the mean ± SD of 6 mice per group. Columns, mean; bars, SD. The symbol “★” indicated a statistical significance with P < 0.05 between the cells transfected with the two different transfectants. (C-E). A549-MKK7-116Glu or A549-MKK7-116Lys cells were separately injected into the tail vein of each mouse. After proximately 10 weeks, lung metastases were evaluated using magnetic resonance imaging, macroscopic observation and histomorphology under microscopy. The red loops and arrows indicate the metastases.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4814107&req=5

pgen.1005955.g003: The effects of MKK7 p.Glu116Lys on tumor growth and metastasis.(A, B). Subcutaneously implanted MKK7-116Glu (A549-MKK7-116Glu and L78-MKK7-116Glu cells) and MKK7-116Lys (A549-MKK7-116Lys and L78-MKK7-116Lys cells) cells xenografted tumors were established and were observed for a total of 4 weeks. Tumor volumes represented the mean ± SD of 6 mice per group. Columns, mean; bars, SD. The symbol “★” indicated a statistical significance with P < 0.05 between the cells transfected with the two different transfectants. (C-E). A549-MKK7-116Glu or A549-MKK7-116Lys cells were separately injected into the tail vein of each mouse. After proximately 10 weeks, lung metastases were evaluated using magnetic resonance imaging, macroscopic observation and histomorphology under microscopy. The red loops and arrows indicate the metastases.
Mentions: To further determine the effect of p.Glu116Lys on tumor growth and metastasis in vivo, cells with stably over-expressing MKK7-116Glu or MKK7-116Lys were injected into nude mice subcutaneously (both for A549 and L78 cell lines), and intravenously (for A549 cell line only), respectively. As is shown in Fig 3A, the injection of MKK7-116Lys cells resulted in tumor formation began 4 days earlier compared to the results from injection of MKK7-116Glu cells. The tumor grew faster, and after 4 weeks, the tumor size in the former group was larger than the latter group (For A549: 1246.3±102.3 mm3vs. 846.3±78.5 mm3, P <0.001, Fig 3A; for L78: 1474.5±99.4 mm3vs. 921.1±88.4 mm3, P <0.001, Fig 3B). Moreover, we used the MRI and histology examination to determine whether the MKK7 p.Glu116Lys could cause tumor metastases, and found that all the mice injected with A549 cells over-expressing MKK7-116Lys suffered from pulmonary metastasis, while the mice group injected with MKK7-116Glu A549 cells did not (Fig 3C, 3D and 3E). These findings demonstrated that MKK7-116Lys variant enhanced lung tumor growth and metastasis in vivo.

Bottom Line: Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology.We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis.These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis.

View Article: PubMed Central - PubMed

Affiliation: The State Key Lab of Respiratory Disease, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, Guangzhou, People's Republic of China.

ABSTRACT
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70-4.01). These rare variants strengthened patients' clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32-1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.

Show MeSH
Related in: MedlinePlus