• Archives of Pharmacal Research
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• 제29권3호
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• pp.235-240
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• 2006

The oral administration of extracts of young radishes cultivated with sulfur after intravenous tumor cell injection achieved a marked reduction of pulmonary colonization in mice. Treatment of the mice with extracts of young radish cultivated with sulfur did not show any increase in the number of CD8+ or NK T cells in the spleen, indicating no influence on host immunity. Sulforaphane, which could be a candidate for an active compound from young radishes cultivated with sulfur, inhibited cell growth of B16-F10 melanoma cells. In addition, extracts of the young radish cultivated with sulfur-fed group showed enhanced quinine reductase (QR) activities in the liver and lung and a slight increase of glutathione S-transferase (GST) activity in the liver. These results suggested that the administration of extracts of young radishes cultivated with sulfur suppressed pulmonary tumorigenesis, possibly due to increased activity of detoxification enzymes in the liver and lung, and partly due to cell cytotoxicity.

• Genomics & Informatics
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• 제16권4호
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• pp.18.1-18.9
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• 2018

Long non-coding RNAs (lncRNAs) are classified as RNAs that are longer than 200 nucleotides and cannot be translated into protein. Several studies have demonstrated that lncRNAs are directly or indirectly involved in a variety of biological processes and in the regulation of gene expression. In addition, lncRNAs have important roles in many diseases including cancer. It has been shown that abnormal expression of lncRNAs is observed in several human solid tumors. Several studies have shown that many lncRNAs can function as oncogenes in cancer development through the induction of cell cycle progression, cell proliferation and invasion, anti-apoptosis, and metastasis. Oncogenic lncRNAs have the potential to become promising biomarkers and might be potent prognostic targets in cancer therapy. However, the biological and molecular mechanisms of lncRNA involvement in tumorigenesis have not yet been fully elucidated. This review summarizes studies on the regulatory and functional roles of oncogenic lncRNAs in the development and progression of various types of cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제27권6호
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• pp.521-531
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• 2023

Transmembrane protein TMEM16A, which encodes calcium-activated chloride channel has been implicated in tumorigenesis. Overexpression of TMEM16A is associated with poor prognosis and low overall survival in multiple cancers including lung adenocarcinoma, making it a promising biomarker and therapeutic target. In this study, three structure-related sesquiterpene lactones (mecheliolide, costunolide and dehydrocostus lactone) were extracted from the traditional Chinese medicine Aucklandiae Radix and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on the proliferation and migration of lung adenocarcinoma cells were examined. Whole-cell patch clamp experiments showed that these sesquiterpene lactones potently inhibited recombinant TMEM16A currents in a concentration-dependent manner. The half-maximal concentration (IC50) values for three tested sesquiterpene lactones were 29.9 ± 1.1 µM, 19.7 ± 0.4 µM, and 24.5 ± 2.1 µM, while the maximal effect (E_max) values were 100.0% ± 2.8%, 85.8% ± 0.9%, and 88.3% ± 4.6%, respectively. These sesquiterpene lactones also significantly inhibited the endogenous TMEM16A currents and proliferation, and migration of LA795 lung cancer cells. These results demonstrate that mecheliolide, costunolide and dehydrocostus lactone are novel TMEM16A inhibitors and potential candidates for lung adenocarcinoma therapy.

• 생명과학회지
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• 제29권6호
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• pp.645-652
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• 2019

전세계적으로 폐암 발병율은 서서히 감소하는 추세이지만, 여전히 암 관련 사망의 주요 원인으로 지목되고 있으며, 이에 따라 폐암 진단과 치료를 위한 새로운 분자적 지표를 발굴하는 연구가 활발히 이루어지고 있다. 본 연구진이 수행한 기존 연구에 따르면 폐암 환자에게서는 전사인자 중 하나인 TFAP2C가 높은 비율로 발현되며, 이 전사인자를 통해 폐암 발달에 상당한 영향을 끼치는 것을 확인할 수 있었다. TFAP2C는 다른 유전자들의 발현을 조절하여 암 형성에 기여하게 된다. 마이크로어레이 분석을 통해 TFAP2C에 의해 발현양이 조절되는 잠재적 표적 유전자들을 확인하였고, 특히 TFAP2C siRNA를 처리하였을 때 발현이 감소되는 원암유전자들 중 CDC20과 TRIB3 유전자를 최종적으로 선별하였다. 리얼타임 qRT-PCR과 웨스턴블롯을 통하여 두 유전자가 TFAP2C에 의존적으로 발현됨을 확인하였으며, 세포 생존 분석법을 통하여 CDC20과 TRIB3의 발현 증가가 폐암세포의 세포 증식을 유의미하게 유도하는 것을 확인하였다. 이와 더불어, CDC20과 TRIB3의 과발현이 폐암세포의 세포사멸 수준을 감소시켜 폐암 형성에 관여함을 확인하였다. 본 연구를 통하여 CDC20과 TRIB3가 폐암 형성을 유도할 수 있는 잠재적인 원암유전자로 기능함을 밝힐 수 있었으며, 두 유전자가 폐암 진단을 위한 표적유전자로서의 역할을 수행할 수 있을 것으로 기대한다.

• Tuberculosis and Respiratory Diseases
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• 제63권2호
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• pp.165-172
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• 2007

폐암의 발생은 여러 많은 유전자의 변화가 축적되어 나타나는 일련의 과정에 의한다. 세포 내 전사 조절 인자의 하나인 CBP는 폐를 포함한 인체 내 여러 조직에서 상피세포의 분화 및 증식에 중요한 역할을 담당하며, 유전자들에서 전사조절인자로서 세포의 성장에 관여하며 발암 과정에서도 중요할 것으로 기대된다. 이에 아직까지 폐암에서 CBP에 대한 연구가 확정된 바가 없어, 폐의 전암성 병변(상피 화생 20예, 이형성증 40예) 및 편평상피세포폐암 60예를 대상으로 하여 CBP의 발현정도를 면역화학적 방법으로 비교 분석하여 다음과 같은 결과를 얻었다. 1) 화생성 병변(7예; 35%)에 비해 이형성 병변(26례; 65%)이나 편평세포암종(42례; 70%)에서 CBP의 발현이 유의하게 높았다(p<0.05). 2) 이형성 병변의 경우, 경도의 이형성 병변(20예 중 10예; 50%)보다 고도의 이형성 병변(20예 중 16예; 80%)에서 높은 CBP의 발현율을 보였다(p<0.01). 3) 편평세포암의 분화도별로 살펴보았을 때, 고분화암에서 95%(20예 중 19예), 중등도 분화암에서 85%(20예 중 17예), 저분화 암에서는 30%(20예 중 6예)의 발현율을 보였다(p<0.05). 이상과 같은 결과를 볼 때, CBP는 폐 조직에서 정상 기관지 상피 세포가 전암성 병변으로 변하거나 전암성 병변이 암으로 진행하는 과정에서 중요한 역할을 하는 것으로 보이며, 세포가 암으로의 발전할 수 있는 잠재성을 가늠하는 표지자가 될 수 있을 것으로 보인다.

• Molecules and Cells
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• 제45권10호
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• pp.718-728
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• 2022

Splicing factor B subunit 4 (SF3B4), a component of the U2-pre-mRNA spliceosomal complex, contributes to tumorigenesis in several types of tumors. However, the oncogenic potential of SF3B4 in lung cancer has not yet been determined. The in vivo expression profiles of SF3B4 in non-small cell lung cancer (NSCLC) from publicly available data revealed a significant increase in SF3B4 expression in tumor tissues compared to that in normal tissues. The impact of SF3B4 deletion on the growth of NSCLC cells was determined using a siRNA strategy in A549 lung adenocarcinoma cells. SF3B4 silencing resulted in marked retardation of the A549 cell proliferation, accompanied by the accumulation of cells at the G0/G1 phase and increased expression of p27, p21, and p53. Double knockdown of SF3B4 and p53 resulted in the restoration of p21 expression and partial recovery of cell proliferation, indicating that the p53/p21 axis is involved, at least in part, in the SF3B4-mediated regulation of A549 cell proliferation. We also provided ubiquitination factor E4B (UBE4B) is essential for p53 accumulation after SF3B4 depletion based on followings. First, co-immunoprecipitation showed that SF3B4 interacts with UBE4B. Furthermore, UBE4B levels were decreased by SF3B4 depletion. UBE4B depletion, in turn, reproduced the outcome of SF3B4 depletion, including reduction of polyubiquitinated p53 levels, subsequent induction of p53/p21 and p27, and proliferation retardation. Collectively, our findings indicate the important role of SF3B4 in the regulation of A549 cell proliferation through the UBE4B/p53/p21 axis and p27, implicating the therapeutic strategies for NSCLC targeting SF3B4 and UBE4B.

• Genomics & Informatics
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• 제21권3호
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• pp.30.1-30.13
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• 2023

Ephs belong to the largest family of receptor tyrosine kinase and are highly conserved both sequentially and structurally. The structural organization of Eph is similar to other receptor tyrosine kinases; constituting the extracellular ligand binding domain, a fibronectin domain followed by intracellular juxtamembrane kinase, and SAM domain. Eph binds to respective ephrin ligand, through the ligand binding domain and forms a tetrameric complex to activate the kinase domain. Eph-ephrin regulates many downstream pathways that lead to physiological events such as cell migration, proliferation, and growth. Therefore, considering the importance of Eph-ephrin class of protein in tumorigenesis, 7,620 clinically reported missense mutations belonging to the class of variables of unknown significance were retrieved from cBioPortal and evaluated for pathogenicity. Thirty-two mutations predicted to be pathogenic using SIFT, Polyphen-2, PROVEAN, SNPs&GO, PMut, iSTABLE, and PremPS in-silico tools were found located either in critical functional regions or encompassing interactions at the binding interface of Eph-ephrin. However, seven were reported in nonsmall cell lung cancer (NSCLC). Considering the relevance of receptor tyrosine kinases and Eph in NSCLC, these seven mutations were assessed for change in the folding pattern using molecular dynamic simulation. Structural alterations, stability, flexibility, compactness, and solvent-exposed area was observed in EphA3 Trp790Cys, EphA7 Leu749Phe, EphB1 Gly685Cys, EphB4 Val748Ala, and Ephrin A2 Trp112Cys. Hence, it can be concluded that the evaluated mutations have potential to alter the folding pattern and thus can be further validated by in-vitro, structural and in-vivo studies for clinical management.

• Tuberculosis and Respiratory Diseases
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• 제48권1호
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• pp.24-32
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• 2000

연구배경: MMR 유전자의 불활성화에 의해 야기되는 유전적 불안정성은 발암기전의 한 부류로 인정되고 있다. 저자들은 비소세포폐암의 발암과정에서의 MSI의 역할을 규명하기 위해 비소세포폐암에서 MSI의 빈도 및 MSI 유무에 따른 임상상의 차이를 조사하였다. 대상 및 방법: 근치적 절제술을 받은 비소세포폐암 20예를 대상으로 하였다. 동결된 폐암조직과 환자의 림프구에서 DNA를 추출한 후 3p와 9p의 15개의 marker들을 대상으로 PCR을 시행하고 7% polyacrylamide gel에서 전기영동한 후 silver 염색을 시행하였다. 암조직과 림프구 DNA의 PCR product의 band를 비교하여 MSI와 LOH를 판정하였다. 결 과: 1) 대상환자들은 남자 19예, 여자 1예였으며 모두 흡연자였고 평균 흡연력은 47 갑년이었다. 폐암의 조직형은 편평상피암 15예, 선암 4예, 대세포암 1예였고, 술후병리학적병기는 I기 6예, II기 5예, IIIA기 7예, IIIB 기 2예였다. 2) 20예 가운데 8예(40%)에서 MSI가 관찰되었으며 3예는 한 개의 marker에서, 5예는 2개 이상의 marker에서 MSI가 관찰되었다. 3) LOH는 10예(50%) 에서 있었으며, LOH 유무에 따른 병기 및 흡연력의 차이가 없었다. 4) 분석한 marker의 10% 이상에서 MSI가 관찰된 MSI-L 종양은 5 예였으며, 대부분의 marker에서 MSI 양성인 MSI-H 종양은 없었다. MSS 종양과 MSI-L 종양은 흡연력, 병기, 폐암 조직형 및 LOH 빈도의 유의한 차이가 없었다. 결 론: 비소세포폐암에서 MSI는 비교적 흔히 관찰되지만 MMR 유전자의 불활성화에 의한 MMP pathway는 비소세포폐암의 주요 발생기전은 아닐 것으로 생각된다. 향 후 비소세포폐암의 발암과정에 있어서 MMP pathway의 역할을 규명하기 위해서는 보다 많은 예를 대상으로 한 연구가 필요할 것으로 생각되며, MSI 발생기전에 관한 추가적인 연구가 필요할 것으로 생각된다.

• Molecules and Cells
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• 제24권3호
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• pp.409-415
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• 2007

The retinoblastoma (Rb) gene is one of the most important genes in cell cycle regulation and tumorigenesis. Homozygosity for a germ-line Rb mutation results in embryonic lethality and evokes developmental defects associated with inappropriate S-phase entry and high levels of apoptosis. Although Rb has been extensively studied, more target genes need to be identified and characterized to unravel the precise mechanism of Rb function. In order to identify Rb-regulated genes, we analyzed the gene expression profile of Rb-deficient mouse embryo fibroblasts (MEFs), and identified an unknown gene, RbEST47, that is transcriptionally upregulated in Rb-deficient MEFs. This gene is conserved from fruitfly to human. It is expressed in brain, lung, kidney, and testis, and is located on mouse chromosome 2. This region is syntenic to human chromosome 9q34.3, which frequently exhibits loss of heterozygosity in neoplastic diseases. RbEST47 was considerably down-regulated in immortalized cells, and showed cell cycle-dependent expression, suggesting important roles in S and/or G2.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.507-510
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• 2013

Background: More and more research indicate that the immediately early response gene 3 (IER3) is involved inmany biological provesses, such as apoptosis and immunoreaction, as well as viral infection, tumorigenesis and tumour progression. Methods: Here we describe the construction of an eukaryotic expression vector containing IER3 gene and its expression in A549 cells as assessed through fluorescence microscopyand Western-blotting. Results: Fluorescence detection displayed that GFP in cytoplasm was high during 48 and 72 hours post-transfection. In addition, Western blotting showed significant increase in IER3 gene expression in the transfected cells compared with controls. Conclusion: The recombinate plasmid expression vector was constructed successfully, which may provide a basis for further exploration of function of IER3 in lung cancer.