Young Yiul Lee

PTTG1 Oncogene Promotes Tumor Malignancy via Epithelial to Mesenchymal Transition and Expansion of Cancer Stem Cell Population

Background: PTTG1 is an oncogene with its expression levels correlating with tumor development and metastasis. Results: Modulation of PTTG1 expression levels revealed that PTTG1 promotes invasive and migratory properties and expansion of CD44high CD24low cell population via AKT activation in breast cancer cells. Conclusion: PTTG1 induces EMT and promotes cancer stem cells via activation of AKT. Significance: PTTG1 represents a potential target for therapeutic intervention against the spread of breast cancer. The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCF7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44high CD24low cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer.

Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer.

Choi JH, Song YS, Yoon JS, Song KW, Lee YY. Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation and metastasis in gastric cancer. APMIS 2010; 118: 196–202.

Non-A type nucleophosmin 1 gene mutation predicts poor clinical outcome in de novo adult acute myeloid leukemia: differential clinical importance of NPM1 mutation according to subtype

Mutations of nucleophosmin gene (NPM1) are known to be related to good prognosis in AML patients lacking FLT3 internal tandem duplication (FLT3-ITD). Recently, NPM1 mutations other than type A were reported, but their clinical significance is not well known. Retrospective medical record review of 106 de novo AML patients lacking FLT3-ITD, who received induction chemotherapy from three centers in Korea between 1997 and 2007, was performed. Direct sequencing of NPM1 and RT-PCR for FLT3-ITD was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for detection of mutations. NPM1 mutation was detected in 18 patients, where 13 were type A mutants and 5 were non-type A mutants. CR, CR1-D and OS was not different according to NPM1 mutational status overall. But, non-type A NPM1 mutation was related to shorter CR1-D when compared with NPM1 wild types and NPM1 type A mutation (p = 0.004). OS was shorter in non-type A mutants when compared with NPM1 wild-type patients and NPM1 type A mutants (p = 0.001). The type of mutation of NPM1 is important for prognosis in de novo AML lacking FLT3-ITD. Non-A type NPM1 mutation is a poor prognostic factor.

Phloroglucinol suppresses metastatic ability of breast cancer cells by inhibition of epithelial-mesenchymal cell transition.

Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF‐1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.

Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration.

Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti‐malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti‐cancer effect of autophagy inhibition, using chloroquine together with 5‐fluorouracil (5‐FU) in a colon cancer cell line. Human colon cancer DLD‐1 cells were treated with 5‐FU (10 μΜ) or chloroquine (100 μΜ), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule‐associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3‐II protein increased after treatment with 5‐FU, and chloroquine potentiated the cytotoxicity of 5‐FU. MTT assays showed that 5‐FU inhibited proliferation of the DLD‐1 cells and that chloroquine enhanced this inhibitory effect of 5‐FU. The combination of 5‐FU and chloroquine induced G1 arrest, up‐regulation of p27 and p53, and down‐regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti‐cancer effect of 5‐FU via cell cycle inhibition. Chloroquine potentiates the anti‐cancer effect of 5‐FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality.

The role of leptin in gastric cancer: clinicopathologic features and molecular mechanisms.

Obesity is associated with certain types of cancer, including gastric cancer. However, it is still unclear whether obesity-related cytokine, leptin, is implicated in gastric cancer. Therefore, we aimed to investigate the role of leptin in gastric cancer. The expression of leptin and its receptor, Ob-R, was assessed by immunohistochemical staining and was compared in patients with gastric adenoma (n=38), early gastric cancer (EGC) (n=38), and advanced gastric cancer (AGC) (n=38), as a function of their clinicopathological characteristics. Gastric cancer cell lines were studied to investigate the effects of leptin on the signal transducer and activator of transcription-3 (STAT3) and extracellular receptor kinase 1/2 (ERK1/2) signaling pathways using MTT assays, immunoblotting, and inhibition studies. Leptin was expressed in gastric adenomas (42.1%), EGCs (47.4%), and AGCs (43.4%). Ob-R expression tended to increase from gastric adenoma (2%), through EGC (8%), to AGC (18%). Leptin induced the proliferation of gastric cancer cells by activating STAT3 and ERK1/2 and up-regulating the expression of vascular endothelial growth factor (VEGF). Blocking Ob-R with pharmacological inhibitors and by RNAi decreased both the leptin-induced activation of STAT3 and ERK1/2 and the leptin-induced expression of VEGF. Leptin plays a role in gastric cancer by stimulating the proliferation of gastric cancer cells via activating the STAT3 and ERK1/2 pathways.

The Primary Extra-gastrointestinal Stromal Tumor of Pleura: A Case Report and a Literature Review

The gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract. The gastrointestinal stromal tumor universally expresses KIT and DOG-1 and frequently harbors oncogenic mutations in the KIT gene. While the gastrointestinal stromal tumor usually arises in the alimentary tract, it is rarely found in the extragastrointestinal area. When it is, it is called an extragastrointestinal stromal tumor. Although the pathogenesis, prognostic factors and outcomes of gastrointestinal stromal tumors are well known, those of extragastrointestinal stromal tumors have not been fully studied. We report, herein, a unique primary extragastrointestinal stromal tumor from the pleura in a 73-year-old woman who presented with pleural mass. The extragastrointestinal stromal tumor was surgically resected and confirmed by means of an immunohistochemical study and a molecular analysis.

Development of acute myocardial infarction in a young female patient with essential thrombocythemia treated with anagrelide: a case report.

Essential thrombocythemia (ET) is a chronic myeloproliferative disorder with a prolonged clinical course. Since this disorder is considered to be at increased risk of thromboembolism, therapy is mainly focused on the decreased risk of thrombohemorrhagic events by use of cytotoxic agents. Anagrelide is a phosphodiesterase III inhibitor which is utilized in the treatment of ET for the reduction of platelets. However, patients treated with anagrelide might experience cardiovascular adverse effects including myocardial infarction (MI), although these events are rare. Herein, we report a case of a 30-year-old female with well controlled ET by anagrelide, who eventually developed an acute non-ST elevation myocardial infarction (MI). There has no found any cardiovascular risk factors in this ET patient, strongly suggesting that anagrelide might be the cause of MI. Therefore, cardiovascular function should be monitored in those patients prescribed with anagrelide.

Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside

Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti-leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-κB, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001-induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time-dependent manner in HL-60 and HL-60R cells. Real‑time PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, γ-H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting.

A case of severe chronic active Epstein-Barr virus infection with T-cell lymphoproliferative disorder.

The Epstein-Barr virus (EBV) is an ubiquitous human herpesvirus that mainly infects B-cells. After primary infection, EBV can induce both replicative (productive or lytic) and latent (persistent) infections in lymphocytes. Latent EBV infection is linked to the development of severe chronic active EBV (SCAEBV) infection with T-cell/natural killer cell (T/NK-cell) lymphoproliferative disorder (LPD) [1]. SCAEBV infection with T-cell LPD is characterized by persistent or recurrent infectious mononucleosis (IM)-like symptoms: high titers of anti-EBV antibodies, the presence of EBV genomes in affected tissues, including peripheral blood, chronic illness that cannot be explained by other known diseases, and monoclonal proliferation of EBV-infected T-cells [2]. In here, we report a case of SCAEBV infection in which T-cell LPD was confirmed by lung biopsy with videoassisted thoracic surgery (VATS) in an adult Korean patient with a history of follicular lymphoma (FL). A 57-year-old man was admitted to Korea Cancer Center Hospital with the chief complaint of intermittent fever for four months. He had lost 5 kg weight over a period of 2 months and had a sore throat, night sweating, and intermittent uveitis. Approximately 4 years prior to his admission to our hospital, he was diagnosed with FL (histologic grade 3, Ann Arbor stage IIA) involving both tonsils and both internal jugular chain lymph nodes. A complete response (CR) was achieved after six cycles of therapy with rituximab, cyclophosphamide, vincristine, and prednisolone followed by radiation therapy, and the CR status was maintained by the patient for 3 years. Therefore, we initially suspected FL recurrence or FL transformation to diffuse large B-cell lymphoma (DLBL). Imaging studies revealed the presence of multi-