전이대장암의 Osteopontin 및 MMP-1 유전자의 발현 변화

의과학과/석사[한글] 전이는 악성종양의 주요 특징으로서 각종 암의 예후와 관련된 가장 중요한 인자로 알려져 있다. 전이과정은 다단계로 이루어지고, 따라서 각 단계를 구성하고 조절하는 유전자적 변화와 유전자 산물의 변화 역시 매우 다양할 것으로 생각된다. 연구자들은 이전에 원발성 대장암과 전이 대장암 조직에서 19,000개 유전자의 human oligonucleotide microarray를 통하여 유전체 발현 양상을 검정하여 원발성 대장암과 전이 대장암 사이에 약 80 여개의 다르게 표현되는 유전자를 발굴한 바 있다. 밝혀진 80여 개의 유전자 중 많은 부분은 기존에 알려진 종양의 전이관련 행태와 관련 있을 것으로 추정되는 것들로, 세포 내외 기질의 합성과 분비, turn over 등에 관련되는 물질이었으며, 이들 중 일부는 종양 생성과 전이 등에 관련이 있음이 타 종양에서도 발견되어 장기와 관련 없이 암종의 전이에 공통적으로 관여할 것으로 추정되었다. 전이의 임상적 의의를 고려해 보았을 때, 이들의 발현 및 조절 양상을 이해하는 것은 필수적인 일이다. 본 연구에서는 이 들 중 Osteopontin, MMP-1, serpin A1의 발현을 동일 환자에서 발생한 검증용 원발성 대장암과 전이 대장암 43세트를 대상으로 면역조직화학염색을 실시하였으며, 이들 중 Osteopontin과 MMP-1이 원발성 대장암과 전이 대장암에서 발현의 차이를 보였다. 따라서 Osteopontin과 MMP-1은 전이 대장암에서 발현이 차이가 나는 중요한 유전자로서 이의 임상적 응용에 관한 연구가 필요하다. [영문] Metastasis is one of the most important characteristics of cancer in terms of its impact on the prognosis such as patient survival. However, understanding of the cellular and molecular mechanism of metastasis is still limited due to intrinsic complexity of mechanism governing whole process. Using high-throughput microarray using 19K spotted human oligonucleotides, gene expression of primary and matched metastatic colon cancer was compared in previous study. Although it did not demonstrate complete classification of primary and metastatic carcinoma, 80 differentially expressed genes have been identified. Among these, expression of Osteopontin, MMP-1 and serpin A1 have been assessed in 43 paired validation set of tissue microarray using immunohistochemistry. The expression of Osteopontin is significantly higher in metastatic carcinoma than primary carcinoma, as mRNA expression is. The expression of MMP-1 is significantly lower in metastatic carcinoma than primary. However, expression of serpin A1 is not correlated with the result from microarray. Thus, the expression of Osteopontin and MMP-1 successfully classify primary and metastatic colorectal carcinoma in the validation set and further studies on their clinical application should be followed accordingly.ope

새롭게 개발된 바이구아나이드 화합물에 의한 교종 종양구 억제 효과

의과대학/박사Glioblastoma (GBM) is a lethal disease with limited survival in spite of recent therapeutic progress and a new strategy against the disease is being required. Recently, the effect of biguanide derived agents are being suggested as new groups of target in the treatment of malignant tumors and their effect against the tumorsphere (TS) were reported. In this study, I assessed effects of a newly developed biguanide, HL156A, on the properties of glioblastoma tumorsphere (GBM-TS) and survival of orthotopic xenograft animals, to assess the feasibility of this agent, alone or combined with conventional therapeutic agent temozolomide (TMZ), in the treatment of GBM. HL156A, alone and combined with TMZ, exhibited an inhibitory effect on the stemness of GBM-TS, proven by the neurosphere formation assay and the assessment of stemness marker expression, without affecting viability of cells. The invasive property of GBM-TS were inhibited most significantly by the combination treatment, compared with the control and HL156A or TMZ alone-treated groups in 3-dimentional collagen matrix invasion assay. The combination treatment repressed epithelial-mesenchymal transition (EMT) related gene expression. Gene ontology class comparison of TMZ and combination treatment group revealed altered expression of gene sets involving cellular adhesion and migration. The combined treatment of HL156A and TMZ showed survival benefits in the orthotopic xenograft mouse model. Targeting of GBM-TSs by the combination of HL156A and TMZ, through the inhibition of stemness and invasion properties of GBM- TS, can be a novel candidate for the treatment of GBM.ope

Novel sunitinib strategy in metastatic renal cell carcinoma on hemodialysis: intermittent dose of sunitinib after hemodialysis.

The proper dose and schedule of sunitinib have yet to be established for patients with metastatic renal cell carcinoma (RCC) on hemodialysis. We reviewed two patients with metastatic RCC on hemodialysis who had been treated with sunitinib in Yonsei Cancer Center, Yonsei University College of Medicine. Fifty milligrams of sunitinib was administered intermittently after each hemodialysis session (3 or 4 times a week). Overall responses were partial response in both cases. Progression-free survivals were 16 and 6 months, respectively, at the time of reporting (April 2010). Both subjects tolerated the treatment.ope

Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis

Proteasomes play important roles in a variety of cellular processes such as cell cycle progression, signal transduction and immune responses. Proteasome activity is important in maintaining rapid turnover of short-lived proteins, as well as preventing accumulation of misfolded or damaged proteins. Alteration in ubiquitin-proteasome function may be detrimental to its crucial role in maintaining cellular homeostasis. Here, we have found that treatment of pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, resulted in the accumulation of several proteasome substrates including p53 and p21 in HeLa cells. The PDTC effect was due to an extended half-life of these proteins through the mobilization of zinc. PDTC and/or zinc also increased fluorescence intensity of UbG76V-GFP fusion protein that is degraded rapidly by the ubiquitin-proteasome system. Treatment of cells with zinc induced formation of ubiquitinated inclusions in the centrosome, a histological marker of proteasome inhibition. Western blotting showed zinc-induced increase in laddering bands of polyubiquitin-conjugated proteins. In vitro study, zinc inhibited the ubiquitin-independent proteasomal degradations of p21 and α-synuclein. These results suggest that zinc may modulate cell functions through its action on the turnover of proteins that are susceptible to proteasome-dependent proteolysis.ope