Cancer Research and Treatment

Original Articles

AKAP12α is Associated with Promoter Methylation in Lung Cancer: Ukhyun Jo, Young Mi Whang, Han Kyeom Kim, Yeul Hong Kim; Cancer Res Treat. 2006;38(3):144-151. Published online June 30, 2006; DOI: https://doi.org/10.4143/crt.2006.38.3.144

Purpose

Promoter methylation is an important mechanism for silencing tumor-suppressor genes in cancer and it is a promising tool for the development of molecular biomarkers. The purpose of the present study was to investigate whether inactivation of the A Kinase Anchoring Protein 12 (AKAP12) gene is assoCiated with promoter methylation in lung cancer.

Materials and Methods

The AKAP12 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in ten lung cancer cell lines. The methylation status of the AKAP12α promoter was analyzed by performing bisulfite sequencing analysis in ten lung cancer cell lines, twenty four lung tissues and matched normal tissues.

Results

The AKAP12α expression was reduced in 6 of 10 (60%) lung cancer cell lines, whereas the AKAP12β expression was absent in 1 of 10 (10%) lung cancer cell lines. The AKAP12α expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in three lung cancer cell lines. Methylation of CpG island 1 in the AKAP12α promoter was detected in 30% of the lung cancer cell lines, whereas methylation of CpG island 2 in the AKAP12α promoter was observed in the immortalized bronchial cell line and in all the lung cancer cell lines. In lung tumors, the CpG island 1 in the AKAP12α promoter was infrequently methylated. However, CpG island 2 in the AKAP12α promoter was highly methylated in lung tumors compared with the surrounding normal tissues, and this was statistically significant (p=0.0001).

Conclusion

Our results suggest that inactivation of the AKAP12α expression is assoCiated with DNA methylation of the promoter region in lung cancer, and that AKAP12α may play an important role in lung cancer carcinogenesis.

Citations

Citations to this article as recorded by

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Ke Li, Xuan Wu, Yuan Li, Ting-Ting Hu, Weifeng Wang, Frank J. Gonzalez, Weiwei Liu
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Cancer and Metastasis Reviews.2023; 42(4): 1169. CrossRef
FGF10 Triggers De Novo Alveologenesis in a Bronchopulmonary Dysplasia Model: Impact on Resident Mesenchymal Niche Cells
Sara Taghizadeh, Cho-Ming Chao, Stefan Guenther, Lea Glaser, Luisa Gersmann, Gabriela Michel, Simone Kraut, Kerstin Goth, Janine Koepke, Monika Heiner, Ana Ivonne Vazquez-Armendariz, Susanne Herold, Christos Samakovlis, Norbert Weissmann, Francesca Ricci,
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Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis
Beatriz Andrea Otálora-Otálora, Daniel Alejandro Osuna-Garzón, Michael Steven Carvajal-Parra, Alejandra Cañas, Martín Montecino, Liliana López-Kleine, Adriana Rojas
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Gene expression changes in cervical squamous cancers following neoadjuvant interventional chemoembolization
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Clinica Chimica Acta.2019; 493: 79. CrossRef
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p 53 Expression in Non - Small Cell Lung Cancer: Its relationship to the clinical prognostic factor and smoking history: Moon Kyung Kim, Han Kyeom Kim, In Sun Kim, Joung Ho Han, Seung Jae Huh, Yong Chan Ahn, Dae Yong Kim, Young Mok Shim; J Korean Cancer Assoc. 1999;31(6):1219-1226.

Abstract PDF: PURPOSE
p53 mutations are one of the most common genetic alterations in human lung cancer. Although the prognostic value of mutant p53 is still debated, it is widely accepted as a relatively early genetic event in the development and progression of lung cancer. Moreover, there are growing reports about an association between smoking and p53 mutation, suggesting that the p53 gene could be a target of the smoking associated carcino- genesis in the lung cancer.
MATERIALS AND METHODS
Surgically resected 89 primary non-small cell lung cancers were obtained from May of 1995 to May of 1997. p53 expression and Ki-67 expression were measured by immunohistochemistry, and each p53 expression and smoking amount were compared with Ki-67 expression and other clinical prognostic factors.
RESULTS
Positive p53 expressions were found in 52 (58%) specimens, including 38 (69%) squamous cell carcinomas, 11 (39%) adenocarcinomas, and 3 (50%) large cell carcinomas, and closely associated with male and squamous cell carcinoma. Also close correlation was observed between smoking amount and p53 expression by the regression analysis. But p53 and Ki-67 expression showed no associations in pathologic stage and survival, and there was no association between p53 expression and survival after adjuvant radiotherapy.
CONCLUSION
Smoking seems to affect p53 mutations in non-small cell lung cancer, and additional efforts are needed to evaluate the carcinogesis of lung cancer.

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Morphologic Changes and Ha - ras Mutation in DMBA - treated Rat Mammary Tissues: Yong Hoon Kim, Hyun Deuk Cho, Kwang II Kim, Joo Han Lee, Hyun Ho Lee, Young Sik Kim, Han Kyeom Kim, In Sun Kim; J Korean Cancer Assoc. 1999;31(6):1140-1150.

Abstract PDF: PURPOSE
To understand the morphologic and molecular changes in carcinogen-induced breast tissues, DMBA (10-dimethy1-1,2 benzanthracene) was administrated in Sprague- Dawley female rats.
MATERIALS AND METHODS
At 50 days of age, all experimental rats were given 20 mg DMBA by gastric intubation. Until the seventh week after DMBA administration, six rats were sacrificed every week, thereafter all tumors found during 20 weeks were removed every week. The morphologic changes were evaluated in routinely processed sections stained with H-E and with anti-smooth muscle actin antibody. Mutation of Ha-ras codons 12 and 61 was examined by ARMS (amplification refractory mutation system) method in frozen tissues.
RESULTS
The epithelial cell proliferation of terminal end buds began 2 weeks after DMBA treatment and progressed to the 6th week, resulting in microscopic malignant tumor in one of the 7th weeks rats. The tumors were developed in 43 of 62 rats (69.4%); 8 benign lesions in 4 rats and 72 malignant tumors in 39 rats. Mutations in the 12th and 61th codon of Ha-ras gene were respectively found in 29.7% and 2.7% of preneoplastic breasts, 25% in benign lesions, 2.6% and 31.6% of malignant tumors.
CONCLUSION
DMBA treatment in rats induced epithelial proliferation, then benign and malignant tumors through Ha-ras gene mutation, especially in codon 61 leading to cancer.

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TGF-beta-1 Expression and p53 Mutation in Non-small Cell Carcinomas of the Lung: Han Kyeom Kim, Seol Hee Park, Young Soon Na, Yong Gu Kang, Young Sik Kim, Jung Ho Han, Mee Ja Park, Insun Kim; J Korean Cancer Assoc. 1997;29(6):1022-1031.

Abstract PDF: PURPOSE
TGF-beta-1 is actually a major growth inhibitor for most cell types. We assumed that the loss of TGF-beta-1 would be occurred during carcinogenesis of the lung. Also, the mutation and expression of p53 have been known to be major moleclar change of non-small cell carcinoma of the lung. So, the relationship between the mutation of p53 and the expression of TGF-beta-1 in the non-small cell carcinomas were evaluated.
MATERIALS AND METHODS
In 43 non-small cell carcinoma and normal tissue of the lung, their TGF-beta-1 mRNA were measured by RT-PCR and p53 was studied by SSCP and Western blotting assay.
RESULTS
p53 mutation rate in non-small cell carcinomas of the lung (48.4%) was much more frequent than the normal control group (14.3%). The expression rate of TGF-beta-1 in lung carcinomas, especially squamous cell carcinoma (71.4%), was much higher than the normal control group (42.9%). p53 mutation and TGF-beta-1 mRNA in the lung carcinomas were not strongly correlated.
CONCLUSION
It suggests that high expression rate of TGF-beta-1 and p53 mutation are associated with carcinogenesis of non-small cell carcinoma of the lung. High expression rate of TGF-beta-1 in the lung carcinomas can be partly explained by the fact that TGF-beta-1 have capacity to control the production of many components of the extracellular matrix and enhance angiogenesis in favor of tumor growth despite of their inhibitory effects of cell growth. However, additional research is required to determine the exact role of TGF-beta-1 in carcinogenesis of the lung.

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Evaulation of Angiogenesis and Matrix Metalloproteinase as Prognostic Markers in Squamous Cell Carcinoma of the Lung: Young Sik Kim, Young Bae Kim, Dong Hwan Shin, Han Kyeom Kim, Bum Woo Yeom, Jong Sang Choi, Insun Kim, Dale Lee; J Korean Cancer Assoc. 1997;29(5):816-824.

Abstract PDF: PURPOSE
In squamous cell carcinomas of the lung, the angiogenesis and the expression rates of metalloproteinase were measured to examine whether they can be useful as prognostic markers and therapeutic potentials.
MATERIALS AND METHODS
The angiogenesis and the expression rates of metalloproteinase were analyzed by counting the number of microvessels and immunohistochemically positive cells of MMP-1 and MMP-2 in 54 squamous cell carcinoma, respectively.
RESULTS
Lymph node meatastasis group showed higher angiogenesis than non-metastasis one (p=0.008). Angiogenesis were elevated with increasing clinical stage. However, MMP-1 and MMP-2 expression rate as the presence or absence of lymph node metastasis and the clinical stages were statistically insignificant, respectively. Angiogenesis failed to demonstrate any significant correlation with the expression rates of MMPs.
CONCLUSION
Our results suggests that angiogenesis level may provide informaton relevant to prognosis as well as treatment decisions.

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