• Molecules and Cells
• /
• v.26 no.4
• /
• pp.329-337
• /
• 2008

Src-family kinases are critically involved in the control of cytoskeleton organization and in the generation of integrin-dependent signaling responses, inducing tyrosine phosphorylation of many signaling and cytoskeletal proteins. Activity of the Src family of tyrosine kinases is tightly controlled by inhibitory phosphorylation of a carboxy-terminal tyrosine residue, inducing an inactive conformation through binding with its SH2 domain. Dephosphorylation of C-ter tyrosine, as well as its deletion of substitution with phenylalanine in oncogenic Src kinases, leads to autophosphorylation at a tyrosine in the activation loop, thereby leading to enhanced Src activity. Beside this phophorylation/dephosphorylation circuitry, cysteine oxidation has been recently reported as a further mechanism of enzyme activation. Mounting evidence describes Src activation via its redox regulation as a key outcome in several circumstances, including growth factor and cytokines signaling, integrin-mediated cell adhesion and motility, membrane receptor cross-talk as well in cell transformation and tumor progression. Among the plethora of data involving Src kinase in physiological and pathophysiological processes, this review will give emphasis to the redox component of the regulation of this master kinase.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.23 no.4
• /
• pp.295-305
• /
• 2001

Protein kinase C (PKC) is known to play a pivotal role in neoplastic transformation cells and its high expression is often found in a variety of types of tumors including oral cancer. While PKC is associated with the altered signal transduction pathway of the tumor cells, it is still unclear which isoform is involved in the carcinogenesis process. Since the cellular distributions and the roles of PKC are isoform-specific, it is very important to identify the specific target molecules to improve our understanding of the carcinogenesis processes. Thus, the present study attempted to perform chemical carcinogen-induced neoplastic transformation of human epithelial cells and analyze the specific isoform of PKCs involved in the cellular transformation. The study analyzed overall PKC responses upon MNNG(N-Methyl-N'-nitro-N-nitroso guanidine) exposure with [$^3H$] PDBu binding assay. PKC translocation was observed at high doses of MNNG treatment in the presence of extracellular calcium. Such effects were not observed in the absence of extracellular calcium. Translocational effects with exposure of MNNG was further enhanced in the presence of hydrocortisone. The result suggests that the type of PKC involved may be $Ca^{2+}$-dependent classical isoform and steroid hormone enhances PKC activation. Among cPKC isoforms examined, only $PKC-{\alpha}$ and r showed significant translocation of protein levels from cytosolic fraction to membrane fraction, as analyzed by immunoblot. $PKC-{\varepsilon}$ in nPKC class showed an inch·eased translocation, but other forms in this class did not show the effect. None of isoforms in aPKC class was affected by MNNG treatment. The study demonstrated that there was a certain specificity in the patterns of isoform induction follwong chemical carcinogen exposure and helped identify all the types of PKC isoforms expressed in human epithelial cells. It was revealed that PKC isoforms were activated in an early resonse to chemical carcinogen, suggesting that PKC be associated with carcinogenesis process from an early stage in this particular cell system. The study will contribute to improving our understanding of chemical-induced carcinogenesis in human cells and may provide a scientific basis to introduce the specific PKC inhibitors as an anticancer drug of epithelial cell-origin cancers including oral cancer.

• Tuberculosis and Respiratory Diseases
• /
• v.75 no.3
• /
• pp.95-103
• /
• 2013

Background: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms. Methods: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment. Results: Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib. Conclusion: NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.

• BMB Reports
• /
• v.54 no.1
• /
• pp.44-58
• /
• 2021

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers.

• The Korean Journal of Cytopathology
• /
• v.7 no.1
• /
• pp.23-30
• /
• 1996

Chromatin texture, which partly reflects nuclear organization, is evolving as an important parameter indicating cell activation or transformation. In this study, chromatin pattern was evaluated by image analysis of the electron micrographs of follicular and papillary carcinoma cells of the thyroid gland and tested for discrimination of the two neoplasms. Digital grey images were converted from the electron micrographs, nuclear images, excluding nucleolus and intranuclear cytoplasmic inclusions, were obtained by segmentation; grey levels were standardized; and grey level histograms were generated. The histograms in follicular carcinoma showed Gaussian or near-Gaussian distribution and had a single peak, whereas those in papillary carcinoma had two peaks(bimodal), one at the black zone and the other at the white zone. In papillary carcinoma, the peak in the black zone represented an increased amount of heterochromatin particles and that at the white zone represented decreased electron density of euchromatin or nuclear matrix. These results indicate that the nuclei of follicular and papillary carcinoma cells differ in their chromatin pattern and the difference may be due to decondensed chromatin and/or matrix substances.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.28 no.2
• /
• pp.166-171
• /
• 2006

Mucoepidermoid carcinoma is a common salivary gland tumor. It comprised 8% of all salivary gland tumor and originated mainly in parotid gland. Central mucoepidermoid carcinoma is rare. It comprised $2{\sim}3%$ of all mucoepidermoid carcinoma, but it occurs in the mandible two or three times more frequently than in the maxilla. Central Mucoepidermoid carcinoma are frequently associated with an odontogenic cyst, such as dentigerous cyst, in which mucous goblet cell would have neoplastic transformation. In May 2002, a 25 year-old male visits in our clinic, presented with a progressive facial swelling after surgical tooth extraction of left mandibular third molar at 1999 in the army. After incisional biopsy, the lesion was confirmed as mucoepidermoid carcinoma so we performed tumor resection and reconstruction surgery of mandible.

• Toxicological Research
• /
• v.14 no.2
• /
• pp.123-127
• /
• 1998

BRCA1 is a tumor suppresser gene in familial cases of breast cancer. It has been controversial whether the subcellular localization of BRCA1 is located in nuclei or cytoplasm in normal human breast cells. We found that a p220 protein was expressed in Type II Normal human breast epithelial cells (NHBEC) but not in Type I NHBEC in Western blot analysis using the 17F8 (3A2) antibody. Immunostaining using the same antibody revealed positive staining in nuclei, cytoplasm and perinuclei of Type II cells and negative staining in Type I NHBEC. The p220 protein, however, was expressed in SV40 immortalized Type I NHBEC and tumorigenic cells derived from them after x-ray and neu oncogene treatment. The subcelluar localization was mostly cytoplasmic and punctate in the nuclei. The breast carcinoma cell lines, MCF-7 and T47D, also expressed the p220 protein. Using RT-PCR, we observed the expression of BRCA1 mRNA in both Type I and Type II NHBEC. This result indicated that there might be mechanisms involved in post-translational or translational regulation of BRCA1 gene. It is speculated that the absence of BRCA1 protein expression in Type I NHBEC might playa role in their susceptibility to neoplastic transformation.

• Clinical and Experimental Reproductive Medicine
• /
• v.19 no.2
• /
• pp.175-179
• /
• 1992

The factors involved in the initial neoplastic transformation and subsquent growth of uterine fibroid are poorly understood. The reduction in uterine fibroid volume associated with the chronic administration of the mechanisms mediating the decrease in fibroid volume in GnRH-a treated patients are poorly defined. The purpose of this study was to determine the proliferating cell nuclear antigen(PCNA) in fibroid from-women pretreated with GnRH analogue(GnRH-a) compared with controls. Tissue was obtained from 16 premenopausal women with uterine fibroid who received GnRH-a(D-Trp6-GnRH) intramusculary every 28 days for four injections. The mean proliferating index(PI) in patients with uterine fibroids was $2.25{\pm}0.9$, and in controls was $8.82{\pm}1.8$(P<0.001). The proliferating index was not corrleated with the reduction of fibroid volume. In this clinical study, although hypoestrogenism may be the main factor that reduce the volume of fibroid, other factors are also considered to be involved in that process. And the regrowth of uterine fibroid may be affected by increased production of PCNA after stopping GnRH-a.

• Korean Journal of Poultry Science
• /
• v.35 no.3
• /
• pp.225-240
• /
• 2008

Marek's disease virus(MDV) is a highly cell-associated, lymphotropic $\alpha$-herpesvirus that causes paralysis and neoplastic disease in chickens. The disease has been controlled by vaccination which was provided the first evidence for a malignant cancer being controlled by an antiviral vaccine. Marek's disease pathogenesis is complex, involving cytolytic and latent infection of lymphoid cells and oncogenic transformation of $CD4^+$ T cells in susceptible chickens. MDV targets a number of different cell types during its life cycle. Lymphocytes play an essential role, although within them virus production is restricted and only virion are produced. Innate and adaptive immune responses develop in response to infection, but infection of lymphocytes results in immunosuppressive effects. Hence in MDV-infected birds, MDV makes its host more vulnerable to tumour development as well as to other pathogens. All chickens are susceptible to MDV infection, and vaccination is essential to protect the susceptible host from developing clinical disease. Nevertheless, MDV infects and replicates in vaccinated chickens, with the challenge virus being shed from the feather-follicle epithelium. The outcome of infection with MDV depends on a complex interplay of factors involving the MDV pathotype and the host genotype. Host factors that influence the course of MD are predominantly the responses of the innate and adaptive immune systems, and these are modulated by: age at infection and maturity of the immune system; vaccination status; the sex of the host; and various physiological factors.

• Korean Journal of Clinical Laboratory Science
• /
• v.39 no.3
• /
• pp.210-216
• /
• 2007

There is increasing evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aim of our study is to analyze the relation between the increase in mast cell number and the expression CD34 and alpha-smooth muscle actin (${\alpha}$-SMA) in the stroma of cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC). We investigated a total of 29 CIN (1,2,3) and 21 SCC (microinvasive and invasive) specimens and compared the distribution of $CD34^+$ stromal cells, ${\alpha}-SMA^+$ cells, transforming growth factor-${\beta}1$ $(TGF-{\beta}1)^+$ cells, and the density of mast cells using immunohistochemistry with antibodies against CD34, ${\alpha}$-SMA, TGF-${\beta}1$, and c-Kit (CD117) respectively. Computerized image analysis was to evaluate the positive area (%) and density of the respective immunoreactive cells. In CIN $CD34^+$ cells were abundant in the stroma but no ${\alpha}-SMA^+$ cells were identified except the wall of blood vessels. $CD34^+$ cells were progressively decreased along the continuum from CIN 2 to microinvasive SCC and not observed in the stroma of invasive SCC. Whereas ${\alpha}-SMA^+$ cells were only observed in the stroma of microinvasive and invasive SCC. We found more intense TGF-${\beta}1$ expression in the increased mast cells in the stroma of invasive SCCs than that in the stroma of CIN. These results indicate that disappearance of $CD34^+$ stromal cells and appearance of ${\alpha}-SMA^+$ cells are associated with the stromal change of CIN to SCC and the transformation of $CD34^+$ stromal cells into ${\alpha}-SMA^+$ cells is mediated by TGF-${\beta}1$ secretions in the stromal mast cell of SCC.