• BMB Reports
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• v.51 no.3
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• pp.119-125
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• 2018

The Hippo pathway plays prominent and widespread roles in various forms of human carcinogenesis. Specifically, the Yes-associated protein (YAP), a downstream effector of the Hippo pathway, can lead to excessive cell proliferation and the inhibition of apoptosis, resulting in tumorigenesis. It was reported that the YAP is strongly elevated in multiple types of human malignancies such as breast, lung, small intestine, colon, and liver cancers. Recent work indicates that, surprisingly, Hippo signaling components' (SAV1, MST1/2, Lats1/2) mutations are virtually absent in human cancer, rendering this signaling an unlikely candidate to explain the vigorous activation of the YAP in most, if not all human tumors and an activated YAP promotes the resistance to RAF-, MAPK/ERK Kinase (MEK)-, and Epidermal growth factor receptor (EGFR)-targeted inhibitor therapy. The analysis of YAP expressions can facilitate the identification of patients who respond better to an anti-cancer drug treatment comprising RAF-, MEK-, and EGFR-targeted inhibitors. The prominence of YAP for those aspects of cancer biology denotes that these factors are ideal targets for the development of anti-cancer medications. Therefore, our report strongly indicates that the YAP is of potential prognostic utility and druggability in various human cancers.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3223-3228
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• 2012

HMGN5 is a typical member of the HMGN (high mobility group nucleosome-binding protein) family which may function as a nucleosomal binding and transcriptional activating protein. Overexpression of HMGN5 has been observed in several human tumors but its role in tumorigenesis has not been fully clarified. To investigate its significance for human lung cancer progression, we successfully constructed a shRNA expression lentiviral vector in which sense and antisense sequences targeting the human HMGN5 were linked with a 9-nucleotide loop. Inhibitory effects of siRNA on endogenous HMGN5 gene expression and protein synthesis were demonstrated via real-time RT-PCR and western blotting. We found HMGN5 silencing to significantly inhibit A549 and H1299 cell proliferation assessed by MTT, BrdU incorporation and colony formation assays. Furthermore, flow cytometry analysis showed that specific knockdown of HMGN5 slowed down the cell cycle at the G0/G1 phase and decreased the populations of A549 and H1299 cells at the S and G2/M phases. Taken together, these results suggest that HMGN5 is directly involved in regulation cell proliferation in A549 and H1299 cells by influencing signaling pathways involved in cell cycle progression. Thus, our finding suggests that targeting HMGN5 may be an effective strategy for human lung cancer treatment.

• Journal of Chest Surgery
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• v.43 no.6
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• pp.588-595
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• 2010

Background: Base on types of tumor, the types of expressed tumor is diverse and the difference in its expression rate is even more various. Due to such reasons an animal model is absolutely needed for a clinical research of lung cancer. The author attempted oncogenesis by cultivating a cell line of non-small cell carcinoma and then injecting it inside thoracic cavities of nude mice. The author conducted quantitative analyses of HER2/neu tumor gene - an epidermal growth factor receptor (EGFR) related to lung cancer, and TGF-${\beta}_1$, which acts as a resistance to cell growth inhibition and malignant degeneration. In order to investigate achievability of the oncogenesis, histological changes and the expression of cancer gene in case of orthotopic lung cancer is necessary. Material and Method: Among 20 immunity-free male BALB/c, five nude mice were selected as the control group and rest as the experimental group. Their weights ranged from 20 to 25 gm (Orient, Japan). After injection of lung cancer line (SW900 G IV) into the pleural cavity of nude mice, They were raised at aseptic room for 8 weeks. HER2/neu was quantitatively analyzed by separating serum from gathered blood via chemiluminiscent immunoassay (CLIA), and immunosandwitch method was applied to quantitatively analyze TGF-${\beta}_1$. SPSS statistical program (SPSS Version 10.0, USA) was implemented for statistical analysis. Student T test was done, and cases in which p-value is less than 0.05 were considered significant. Result: Even after lung cancer was formed in the normal control group or after intentionally injected lung cancer cell line, no amplification of HER2/neu gene showed reaction. However, the exact quantity of TGF-${\beta}_1$ was $28,490{\pm}8,549pg/mL$, and the quantity in the group injected with lung cancer cell was $42,362{\pm}14,449pg/mL$, meaning 1.48 times highly Significant (p<0.483). It proved that HER2/neu gene TGF-${\beta}_1$ had no meaningful interconnection. Conclusion: TGF-${\beta}_1$ gene expressed approximately 1.48 times amplification in comparison to the control group. The amplification of TGF-${\beta}_1$ meant somatic recuperation inhibition mechanism due to carcinogenesis in nude mice was definitely working. It may be implemented as a quantitative analysis that allows early detection of lung cancer in human body.

• Tuberculosis and Respiratory Diseases
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• v.45 no.4
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• pp.776-784
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• 1998

Background: The cyclin D1 gene is one of the most frequently amplified chromosomal regions(11q13) in human carcinomas. In laryngeal and head and neck carcinomas, its overexpression has been shown to be associated with advanced local invasion and presence of lymph node metastases. Cyclin D1 may therefore playa key role in cell growth regulation and tumorigenesis. Lung cancer is a worldwide problem and in many contries it is the most lethal malignancy. As relapse is frequent after resection of early stage non-small cell lung cancer, there is an urgent need to define prognostic factors. Purpose: This study was undertaken to evaluate the prognostic value of the cyclin D1, that is one the G1 cyclins which control cell cycle progression by allowing G1 to S phase transition, on the patients in radically resected non-small cell lung cancer. Method: Total 81 cases of formalin-fixed paraffin-embedded blocks from resected primary non-small cell lung cancer from January 1, 1983 to July 31, 1995 at Hanyang University Hospital were available for both clinical follow-up and immunohistochemical staining using monoclonal antibodies for cyclin D1. Results : The histologic classification of the tumor was based on WHO criteria, and the specimens included 45 squamous cell carcinomas, 25 adenocarcinomas and 11 large cell carcinomas. Cyclin D1 overexpression was noted in 26 cases of 81 cases tested (30.9%). Cyclin D1 expression was not significantly associated with cell types of the tumor, pathological staging and the size of the tumor. But cyclin D1 overexpression was significantly correlated with positive lymph node metastasis(p=0.035). The mean survival duration was $22.76{\pm}3.50$ months in cyclin D1 positive group and $45.38{\pm}5.64$ months in eyclin D1 negative group. There was a nearly significant difference in overall survival between cyclin D1 positive and negative groups(p=0.0515) in radically resected non-small cell lung cancer. Conclusion: Based on this study, cyelin D1 overexpression appears an important poor prognostic indicator in non-small cell lung cancer and may have diagnostic and prognostic importance in the treatment of resectable non-small cell lung cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.1881-1895
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• 2015

Background: The vascular endothelial growth factor family has been implicated in tumorigenesis and metastasis. The prognostic value of each vascular endothelial growth factor family member, particular VEGF/VEGFR co-expression, in patients with non-small lung cancer remains controversial. Materials and Methods: Relevant literature was identified by searching PubMed, EMBASE and Web of Science. Studies evaluating expression of VEGFs and/or VEGFRs by immunohistochemistry or ELISA in lung cancer tissue were eligible for inclusion. Hazard ratios (HRs) and 95% confidence intervals (CIs) from individual study were pooled by using a fixed- or random-effect model, heterogeneity and publication bias analyses were also performed. Results: 74 studies covering 7,631 patients were included in the meta-analysis. Regarding pro-angiogenesis factors, the expression of VEGFA (HR=1.633, 95%CI: 1.490-1.791) and VEGFR1 (HR=1.924, 95%CI: 1.220-3.034) was associated separately with poor survival. Especially, VEGFA over-expression was an independent prognostic factor in adenocarcinoma (ADC) (HR=1.775, 95%CI: 1.384-2.275) and SCC (HR=2.919, 95%CI: 2.060-4.137). Co-expression of VEGFA/VEGFR2 (HR=2.011, 95%CI: 1.405-2.876) was also significantly associated with worse survival. For lymphangiogenesis factors, the expression of VEGFC (HR=1.611, 95%CI: 1.407-1.844) predicted a poor prognosis. Co-expression of VEGFC/VEGFR3 (HR=2.436, 95%CI: 1.468-4.043) emerged as a preferable prognostic marker. Conclusions: The expression of VEGFA (particularly in SCC and early stage NSCLC), VEGFC, VEGFR1 indicates separately an unfavorable prognosis in patients with NSCLC. Co-expression VEGFA/VEGFR2 is comparable with VEGFC/VEGFR3, both featuring sufficient discrimination value as preferable as prognostic biologic markers.

• Journal of Life Science
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• v.21 no.3
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• pp.417-423
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• 2011

Thymosin ${\beta}4$ (TB-4) has been reported to play a key role in tumor growth, metastasis and angiogenesis. In addition, TB-4 induced the expression of vascular endothelial growth factor (VEGF) and stabilized the hypoxia-inducible factor (HIF)-$1{\alpha}$ in melanoma cells. Although the importance of thymosin ${\beta}4$ in angiogenesis and metastasis has been proven, there are few studies that show the expression patterns of TB-4, VEGF and HIF-$1{\alpha}$. This study was conducted to analyze the relationship among these proteins in various tumors. Using tissue microarray analysis, we investigated the expression patterns of TB-4, VEGF and HIF-$1{\alpha}$ in various tumors to identify the expression patterns and relationships of these proteins in certain tumors. TB-4 was highly expressed in osteosarcoma, colon adenocarcinoma, esophageal squamous cell carcinoma, kidney and urinary bladder transitional carcinoma, lung cancer, and liver cancer. HIF-$1{\alpha}$ was highly expressed in nasal cavity inverted papilloma, lung cancer, and esophageal squamous cell carcinoma. The expression patterns of TB-4 and HIF-$1{\alpha}$ were almost similar and co-localized. VEGF expression was high in the blood vessels in tumors, but usually not high in the tumors themselves. VEGF was moderately expressed in stomach cancer, liver angiosarcoma, gall bladder adenocarcinoma, and uterus endometrial adenocarcinoma. The expression patterns of VEGF shows similarities in certain tumors including stomach cancer, osteosarcoma, liposarcoma, lung cancer, liver cancer, gall bladder adenocarcinoma, esophageal squamous cell carcinoma, stomach cancer, colorectal carcinoma and renal cell carcinoma. These results suggest that the expression patterns of TB-4, HIF-$1{\alpha}$ and VEGF were co-localized and related to tumorigenesis and angiogenesis of certain tumors.

• Korean Journal of Food Science and Technology
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• v.33 no.6
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• pp.656-663
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• 2001

The most representative nitrosamine derived from nicotine, nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), has been reported to cause lung cancer in A/J mice. It has been also demonstrated that NNK-induced lung tumorigenesis involves $O^6-methylguanine(O^6MeG)$ formation, leading to $GC\;{\rightarrow}\;AT$ transitional mispairing during DNA replication. Our in vitro experiment, modified from the method of DBA assay, examined the ability of phyto-extract mixture to inhibit the metabolism of nicotine to nitrosamines. The production of nitromorpholine from morpholine was inhibited about 75% at the concentration of 20 mg/mL of phyto-extract mixture, which was lower than vitamine C and green tea powder. NNK, which is a pro-carcinogen in laboratory animals, is hydroxylated primarily in liver and lung by CYP 1A2, 2A6 and 3A4. A critical phase. of NNK activation is its change to an unstable metabolite methyl-diazohydroxide via CYP-mediated ${\alpha}-hydroxylation$; and then it provides a methyl group to the DNA to form DNA adducts which can easily induce mutations. $Aroclor^R$ 1254 was used to induce CYPs in the liver of a Sprague-Dawley rat. The ability of various test samples to inhibit CYPs that participate in NNK activation was evaluated, following the removal of the liver from the rat. Microsomal CYPlA2 catalyzing the conversion of NNK into strong carcinogenic chemicals was inhibited more efficiently by phyto-extract mixture than green tea powder. These results indicate that phyto-extract mixture can be used to reduce $O^6MeG$ DNA adducts for chemoprevention.

• Tuberculosis and Respiratory Diseases
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• v.45 no.5
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• pp.962-974
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• 1998

Background: Alteration of p53 tumor suppressor genes is most frequently identified in human neoplasms, including lung carcinoma. It is well known that bcl-2 oncoprotein protects cells from apoptosis. Recent studies have demonstrated that bcl-2 expression is associated with favorable prognosis for patients with non-small cell lung carcinoma. However, the precise biologic role of bcl-2 in the development of these tumors is still obscure. p53 and bcl-2 have important regulatory influence in the apoptotic pathway and thus their relationship is of interest in tumorigenesis, especially lung cancer. Purpose: The author investigated to know the prognostic significance of the expression of p53 and bcl-2 in radically resected non-small cell lung cancer. Method: 84 cases of formalin-fixed paraffin-embedded blocks from resected primary non-small cell lung cancer from 1980 to 1994 at Hanyang University Hospital were available for both clinical follow-up and immunohistochemical staining using monoclonal antibodies for p53 and bcl-2. Results : The histologic classification of the tumor was based on WHO criteria., and the specimens included 45 squamous cell carcinomas(53.6%), 28 adeonocarcinomas(33.3%) and 11 large cell carcinomas(13.1 %). p53 immunoreactivity was noted in 47 cases of 84 cases(56.0%). bcl-2 immunoreactivity was noted in 15 cases of 84 cases(17.9%). The mean survival duration was $64.23{\pm}10.73$ months in bcl-2 positive group and $35.28{\pm}4$. 39 months in bcl-2 negative group. The bcl-2 expression was significantly correlated with survival in radically resected non-small cell lung cancer patients(p=0.03). The mean survival duration was $34.71{\pm}6.12$ months in p53 positive group and $45.35{\pm}6.30$ months in p53 negative group(p=0.21). The p53 expression was not predictive for survival. There was no correlation between combination of the different status of p53 and bcl-2 expression in our study. Conclusions : The interaction and the regulation of new biologic markers, such as those involved in the apoptotic pathway, are complex. bcl-2 overexpression is a good prognostic factor in non-small cell lung cancer and p53 expression is not significantly associated with the prognostic factor in non-small cell lung cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.255-260
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• 2012

Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)-namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.33-38
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• 2014

Background: Meningiomas are the second most common primary intracranial tumors after gliomas. Epigenetic biomarkers such as DNA methylation, which is found in many tumors and is thus important in tumorigenesis can help diagnose meningiomas and predict response to adjuvant chemotherapy. We investigated aberrant O6-methyl guanine methyltransferase (MGMT) methylation in meningiomas. Materials and Methods: Sixty-one patients were classified according to the WHO grading, and MGMT promoter methylation status was examined via the methylation-Specific PCR(MSP) method. Results: MGMT promoter methylation was found in 22.2% of grade I, 35% of grade I with atypical features, 36% of grade II, and 42.9% of grade III tumors. Conclusions: There was an increase, albeit not statistically significant, in MGMT methylation with a rise in the tumor grade. Higher methylation levels were also observed in the male gender.