인체 폐암조직에서 Phospholipase C-$\gamma1$의 활성화 단백, AHNAK의 발현양상

오윤정,박준성,최소연,정성철,이선민,황성철,이이형,한명호,이기범,류한영,하만준,배윤수,이서구,Oh, Yoon-Jung,Park, Chun-Seong,Choi, So-Yeon,Cheong, Seong-Cheoll,Lee, Sun-Min,Hwang, Sung-Chul,Lee, Yi-Hyeong,Hahn, Myung-Ho,Lee, Kyi-Beom,Ryu, Han 대한결핵및호흡기학회 1999 Tuberculosis and Respiratory Diseases Vol.47 No.3

배경: Phospholipase C(PLC)는 세포의 성장, 분화, 변형(transformation)과 관련된 세포내 신호 전달과정에 중추적인 역할을 하는 효소이다. 이들 중 PLC-$\gamma$는 tyrosine kinase의 인산화에 의해 주로 활성화되는 데, 최근에 phosphatidic acid(PA), phosphatidy-linositol 3, 4, 5-trisphosphate($PIP_3$), tau 단백에 의한 활성화 기전이 밝혀진 바 있다. 특히 tau 단백은 bovine brain에서 arachidonic acid와 함께 PLC-$\gamma$를 활성화시키는 것으로 알려져 PLC-$\gamma$와 $PLA_2$ 사이의 cross-talk이 이루어질 가능성이 제시되고 있다. 최근 보고에 의하면 tau 단백과 같은 기전으로 PLC-${\gamma}1$ 활성화시키는 단백이 bovine lung에서 발견되었고, 이 활성화 단백을 정제 및 클론하여 AHNAK 단백임이 확인된 바 있다. 또한 PLC-${\gamma}1$이 유방암, 대장암, 위암 등에서 증가되어 있어 발암 과정과 연관되어 있음이 보고되어 왔으나 PLC-${\gamma}1$의 활성화 단백인 AHNAK 단백에 대해서는 질병과 관련되어 연구된 것이 아직 없는 실정이며 저자 등은 폐암 조직과 정상 폐조직에서 AHNAK 단백의 발현 양상을 연구하여 폐암의 발암과정에 AHNAK 단백이 관여함을 밝히고자 하였다. 대상 및 방법: 아주대학교 병원에 내원하여 폐암으로 수술을 받은 환자의 폐암 조직과 동일 환자의 정상 폐조직에서 AHNAK 단백의 발현양상을 western blot 분석과 면역조직화학적 염색방법을 통하여 조사하였다. 결과: 14예의 편평상피암 세포조직 중 8예 (57.1 %)와 14예의 선암 세포조직 모두에서 정상 대조군에 비해 AHNAK 단백의 발현이 증가하였고, 70 kDa~200kDa의 여러가지 분자량을 가지는 띠모양으로 나타났다. 면역조직화학적 염색에서도 정상 폐조직보다 폐암 조직내에서 강한 발색반응을 보였다. 결론: PLC-${\gamma}1$의 활성화 단백인 AHNAK 단백이 폐암 조직에서 정상 조직보다 과발현된 것은, AHNAK 단백이 PLC-${\gamma}1$을 활성화시켜 폐암의 발생 기전에 관여할 수 있음을 뒷받침한다고 하겠다. Background: Phospholipase C(PLC) plays a central role in cellular signal transduction and is important in cellular growth, differentiation and transformation. There are currently ten known mammalian isozymes of PLC reported to this date. Hydrolysis of phosphatidylinositol 4,5-bisphosphate($PIP_2$) by PLC produces two important second messengers, inositol 1,4,5-trisphosphate($IP_3$) and diacylglycerol. PLC-${\gamma}1$, previously, was known to be activated mainly through growth factor receptor tyrosine kinase. Other mechanisms of activating PLC-yl have been reported such as activation through tau protein in the presence of arachidonic acid in bovine brain and activation by $IP_3$, phosphatidic acid, etc. Very recently, another PLC-${\gamma}1$ activator protein such as tau has been found in bovine lung tissue, which now is considered to be AHNAK protein. But there has been no report concerning AHNAK and its associated disease to this date. In this study, we examined the expression of the PLC-${\gamma}1$ activator, AHNAK, in lung cancer specimens and their paired normal. Methods: From surgically resected human lung cancer tissues taken from twenty-eight patients and their paired normal counterparts, we evaluated expression level of AHNAK protein using immunoblot analysis of total tissue extract Immunohistochemical stain was performed with primary antibody against AHNAK protein. Results: Twenty-two among twenty-eight lung cancer tissues showed overexpression of AHNAK protein (eight of fourteen squamous cell lung cancers, all of fourteen adenocarcinomas). The resulting bands were multiple ranging from 70 to 200 kDa in molecular weight and each band was indistinct and formed a smear, reflecting mobility shift mainly due to proteolysis during extraction process. On immunohistochemistry, lung cancer tissues showed a very heavy, dense staining with anti-AHNAK protein antibody as compared to the surrounding normal lung tissue, coresponding well with the results of the western blot Conclusion: The overexpression of PLC-${\gamma}1$ activator protein, AHNAK in lung cancer may provide evidence that the AHNAK protein and PLC-${\gamma}1$ act in concerted manner in carcinogenesis.

인체 폐암조직에서 Phospholipase C-γ1의 활성화 단백, AHNAK의 발현양상

류한영 ( Han Young Ryu ),하만준 ( Mahn Joon Ha ),배윤수 ( Yoon Su Bae ),이서구 ( Seo Goo Rhee ),오윤정 ( Yoon Jung Oh ),박준성 ( Chun Seong Park ),최소연 ( So Yeon Choi ),정성철 ( Seong Cheoll Cheong ),이선민 ( Sun Min Lee ),황성 대한결핵 및 호흡기학회 1999 Tuberculosis and Respiratory Diseases Vol.47 No.3

안구돌출과 요붕증으로 나타난 Langerhans 세포 조직구증에 대한 증례 보고

김선신,박준성,신승수,김효철,전미선,박광화 아주대학교 의과학연구소 1999 아주의학 Vol.4 No.1

The authors experienced a case of Langerhans cell histiocytosis who presented with severe exophtalmus and central diabetes insipidus. A 26 year old female patient had exophthalmus on her left side due to Langerhans cell histiocytosis infiltrating the left petrosal and orbital bone demonstrated by MRI. Water deprivation test revealed diabetes insipidus of central type due to Langerhas cell histiocytosis involving the pituitary gland. Exophtalmus improved significantly with VP-16 150 ㎎/㎡/weekly for 6 weeks, vinblastin 6 ㎎/㎡ weekly for 6 weeks, and prednisolone 40 ㎎/㎡/daily for 4 weeks, while diabetes insipidus was controlled by nasal spray of DDAVP.

선택적으로 분리된 CD34 양성 자가 조혈모세포이식 후 면역기능의 회복

이은희,김도현,정재학,박준성,김현수,홍대식,박성규,김형준,홍영선,김춘추,김효철,김원석,박찬형 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.2

연구배경: 자가말초혈액 조혈모세포이식에 있어 CD34 양성세포의 선택적 분리로 인해 1~4 logs 정도의 종양세포의 감소를 가져오며, 또한 CD34 양성세포 이식 후의 면역기능의 회복은 선택적으로 분리되지 않은 자가 조혈모세포이식 시와 거의 비슷하다는 것이 보고되어 왔다. 이에 저자들은 선택적으로 분리된 자가 CD34 양성 조혈모세포이식 후의 면역기능의 회복 양상을 알아보기 위해 다기관 연구를 시행하였다. 방법: 15명의 악성 림프종, 유방암, 다발성 골수종 환자들을 대상으로 고용량 항암요법 후 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식을 시행하였다. 이식 후 1, 2, 4, 6개월에 림프구 표현형 측정과 PHA mitogen induced T세포 증식정도를 측정하였다. 결과: 이식 후 6개월 추적 관찰 시 CD3 양성, CD4 양성 림프구의 수는 정상보다 낮았고, CD8 양성세포는 정상 수준을 보였다. 초기 CD4/CD8 비는 감소되었지만 6개월 후 정상으로 회복되는 경향을 보였으며, CD19 양성, CD56 양성세포수는 정상 수준을 나타냈다. PHA mitogen response는 12개월 추적 관찰 시까지 지속적으로 증가 추세를 보였다. 결론: 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식은 빠르고 지속적인 혈액학적 생착을 유도하는 것을 알 수 있으며, 이는 기존의 연구에서 선택되지 않은 자가 조혈모세포이식 시와 비교하여 면역기능의 회복에는 유의한 차이가 없다는 보고와 일치하는 결과이다. 그러므로 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식을 통해 상당한 T 세포의 감소에도 불구하고 면역기능의 회복에 지연 없이 종양세포의 오염을 줄이는 것이 가능함을 확인하였다. Background: Positive selection of autologous peripheral blood stem cells (PBSC) for CD34-expressing cells permits 1 to 4 logs of tumor cell depletion. Hematologic recovery after CD34+ cell transplatation has been reported to be rapid and similar to results achieved in unselected autologous peripheral blood stem cell transplantation (APBSCT). We performed a multi-center study to evaluate the immune reconstitution after CD34+ immunoselected APBSCT. Methods: Fifteen patients with lymphoma, breast cancer, or multiple myeloma received high dose myeloablative chemotherapy followed by an infusion of CD34+ immunoselected PBSC. On 1, 2, 4, and 6 months after transplantation, lymphocyte phenotype was evaluated by flow cytometry and mitogen-induced T cell proliferation were measured. Results: At 6 months after transplantation, CD3+ lymphocyte subset remained below the normal range. CD4+ lymphocytes were depressed while CD8+ lymphocyte subset was in normal range. As a result, inversion of CD4/CD8 ratio was documented for first 4 months, but after 6 months follow up CD4/CD8 ratio was recovered. CD19+ B lymphocyte subset and CD56+ lymphocytes after CD34+ APBSCT were within the normal range. The PHA mitogen induced response was increased during 12 months' follow-up consistently. Phenotypic and functional reconstitution of immune cells after CD34+ cell transplantation were rapid and similar to previous studies. Conclusion: Transplantation of CD34+ immunoselected PBSC allows rapid and sustained hematologic engraftment, and there was no marked delay of immune reconstitution. The selection of CD34+ cells, although causes an extensive depletion of T lymphocytes in the graft does not represent a delayed immune recovery after transplantation.

다양한 악성 종양에서의 말초혈액조혈 모세포이식을 통한 고용량 항암치료

김현수,구성현,최소연,조요한,지석배,박준성,박희붕,황성철,유희석,전미선,조용관,김효철 대한조혈모세포이식학회 1996 대한조혈모세포이식학회지 Vol.1 No.1

High dose chemotherapy with autologous stem cell transplantation is a new therapeutic strategy for various malignancy, especially leukemia, lymphoma, breast cancer. Recently, increasing number of trials has been done in solid tumors responsive to conventional chemotherapy using high dose chemotherapy and autologous peripheral blood stem cell transplantation. At Ajou University Hospital, between August 1995 and September 1996, 60 patients received high dose chemotherapy with peripheral blood stem cell transplantation, which in cluded 20 stomach cancers, 16 breast cancers, 15 lymphomas, 4 lung cancers, 3 ovarian cancers, 1 cervix cancer and 1 cancer of unknown primary cancer. Median age of patients was 44 years(range, 19 to 66), and male to female ratio was 0.7:1. The median time to recovery to neutrophil count more than 0.5x109/L was 11 days, and platelet count more than 20x109/L and 50x109/L was 13 and 17 days. With high dose chemotherapy in 41 patients who had relapsed or refractory disease, the complete remission was achieved in 34%(14/41) of patients and overall response rate was 83%(34/41). There was high response rate in spite of various tumor and various status of disease. In with stomach cancer and breast cancer who were given HDCT with adjuvant treatment aim, high dose chemotherapy was well tolerated with minimal non-hematogic toxicity and morbidity. During high dose chemotherapy, there was three transplantation related death, 2 sepsis and 1 veno-occlusive disease. Our experience suggest is well tolerated procedure which confers that high dose chemotherapy with peripheral blood transplantation will be a promising treatment modality for the relapsed and refractory tumors, as well as for patients with high risk for relapse following curative surgical resection.