• The Korean Journal of Applied Statistics
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• v.28 no.2
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• pp.343-351
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• 2015

We introduce how to fit random effects models via a SRC-Stat statistical package. This package has been developed to fit double hierarchical generalized linear models where mean and dispersion parameters for the variance of random effects and residual variance (overdispersion) can be modeled as random-effect models. The estimates of fixed effects, random effects and variances are calculated by a hierarchical likelihood method. We illustrate the use of our package with practical data-sets.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.2235-2240
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• 2012

c-Src is one member of non-receptor tyrosine kinase protein family that has over expression and activation in many human cancer cells. It has been shown that c-Src is implicated in various downstream signaling pathways associated with EGFR-dependent signaling such as MAPK and STAT5 pathways. Transactivation of EGFR by c-Src is more effective than EGFR ligands. To inhibit the c-Src expression, we used c-Src antisense oligonucleotide complexed with PAMAM Denderimes. The effect of c-Src antisense oligonucleotide on HT29 cell proliferation was determined by MTT assay. Then, the expression of c-Src, EGFR and the genes related to EGFR-depended signaling with P53 was applied by real time PCR. We used western blot analysis to elucidate the effect of antisense on the level of c-Src protein expression. The results showed, c-Src antisense complexed with PAMAM denderimers has an effective role in decrease of c-Src expression and EGFR-dependent downstream genes.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.418-425
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• 2022

Background: Sorafenib is effective in treating hepatoma, but most patients develop resistance to it. STAT3 signaling has been implicated in sorafenib resistance. Artesunate (ART) and 20(R)-ginsenoside Rg3 (Rg3) have anti-hepatoma effects and can inhibit STAT3 signaling in cancer cells. This study aimed to evaluate the effects of Rg3 in combination with ART (Rg3-plus-ART) in overcoming sorafenib resistance, and to examine the involvement of STAT3 signaling in these effects. Methods: Sorafenib-resistant HepG2 cells (HepG2-SR) were used to evaluate the in vitro anti-hepatoma effects of Rg3-plus-ART. A HepG2-SR hepatoma-bearing BALB/c-nu/nu mouse model was used to assess the in vivo anti-hepatoma effects of Rg3-plus-ART. CCK-8 assays and Annexin V-FITC/PI double staining were used to examine cell proliferation and apoptosis, respectively. Immunoblotting was employed to examine protein levels. ROS generation was examined by measuring DCF-DA fluorescence. Results: Rg3-plus-ART synergistically reduced viability of, and evoked apoptosis in HepG2-SR cells, and suppressed HepG2-SR tumor growth in mice. Mechanistic studies revealed that Rg3-plus-ART inhibited activation/phosphorylation of Src and STAT3 in HepG2-SR cultures and tumors. The combination also decreased the STAT3 nuclear level and induced ROS production in HepG2-SR cultures. Furthermore, overactivation of STAT3 or removal of ROS diminished the anti-proliferative effects of Rg3-plus-ART, and removal of ROS diminished Rg3-plus-ART's inhibitory effects on STAT3 activation in HepG2-SR cells. Conclusions: Rg3-plus-ART overcomes sorafenib resistance in experimental models, and inhibition of Src/STAT3 signaling and modulation of ROS/STAT3 signaling contribute to the underlying mechanisms. This study provides a pharmacological basis for developing Rg3-plus-ART into a novel modality for treating sorafenib-resistant hepatoma.

• The Korean Journal of Applied Statistics
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• v.28 no.2
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• pp.309-324
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• 2015

In this paper we introduce how to analyze survival data via a SRC-Stat statistical package. This provides classical survival analysis (e.g. Cox's proportional hazards models for univariate survival data) as well as advanced survival analysis such as shared and nested frailty models for multivariate survival data. We illustrate the use of our package with practical data sets.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4751-4756
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• 2012

Colon cancer continues to be one of the most common cancers, and the importance and necessity of new therapies needs to be stressed. The most important proto-oncogen factors for colon cancer appear to be epidermal growth factor receptor, EGFR, and c-Src with high expression and activity leading to tumor growth and ultimately to colon cancer progression. Application of c-Src and EGFR antisense agents simultaneously should theoretically therefore have major benefit. In the present study, anti-EGFR and c-Src specific antisense oligodeoxynucleotides were combined in a formulation using PAMAM dendrimers as a carrier. Nano drug entry into cells was confirmed by flow cytometry and fluorescence microscopy imaging and real time PCR showed gene expression of c-Src and EGFR, as well as downstream STAT5 and MAPK-1 with the tumor suppressor gene P53 to all be downregulated. EGFR and c-Src protein expression was also reduced when assessed by western blotting techniques. The effect of the antisense oligonucleotide on HT29 cell proliferation was determined by MTT assay, reduction beijng observed after 48 hours. In summary, nano-drug, anti-EGFR and c-Src specific antisense oligodeoxynucleotides were effectively transferred into HT-29 cells and inhibited gene expression in target cells. Based on the results of this study it appears that the use of antisense EGFR and c-Src simultaneously might have a significant effect on colon cancer growth by down regulation of EGFR and its downstream genes.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.253-259
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• 2016

Previously, we found that KTH-13 isolated from the butanol fraction of Cordyceps bassiana (Cb-BF) displayed anti-cancer activity. To improve its antiproliferative activity and production yield, we employed a total synthetic approach and derivatized KTH-13 to obtain chemical analogs. In this study, one KTH-13 derivative, 4-(tert-butyl)-2,6-bis(1-phenylethyl)phenol (KTH-13-t-Bu), was selected to test its anti-cancer activity. KTH-13-t-Bu diminished the proliferation of C6 glioma, MDA-MB-231, LoVo, and HCT-15 cells. KTH-13-t-Bu induced morphological changes in C6 glioma cells in a dose-dependent manner. KTH-13-t-Bu also increased the level of early apoptotic cells stained with annexin V-FITC. Furthermore, KTH-13-t-Bu increased the levels of cleaved caspase-3 and -9. In contrast, KTH-13-t-Bu upregulated the levels of pro- and cleaved forms of caspase-3, -8, and -9 and Bcl- 2. Phospho-STAT3, phospho-Src, and phospho-AKT levels were also diminished by KTH13-t-Bu treatment. Therefore, these results strongly suggest that KTH-13-t-Bu can be considered a novel anti-cancer drug displaying pro-apoptotic activity.

• Journal of Physiology & Pathology in Korean Medicine
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• v.35 no.5
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• pp.177-184
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• 2021

The root bark of Morus alba L. (MA) used in traditional oriental medicine for the treatment of pulmonary diseases exerts various pharmacological activities including anticancer effects. In the current study, we investigated the effects of MA on the migration and invasion of colorectal carcinoma cells. Results from a transwell assay showed that the methylene chloride extract of MA (MEMA) suppressed the migration and invasion of HCT116 human colorectal carcinoma cells in a concentration-dependent manner. MEMA reduced both mRNA and protein levels of matrix metalloproteinase (MMP)-9, but did not suppress the expression of MMP-2 in HCT116 cells. As a molecular mechanism, MEMA inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38, in a dose-dependent manner. In addition, MEMA dephosphorylated both Src and signal transducer and activator of transcription 3 (STAT3) in HCT116 cells. Taken together, we demonstrate that MEMA suppressed the migration and invasion capacity of HCT116 human colorectal cancer cells by downregulation of MMP-9 and inactivation of both MAPKs and Src/STAT3 signaling pathway.

• Biomolecules & Therapeutics
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• v.20 no.6
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• pp.513-519
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• 2012

Although the immense efforts have been made for cancer prevention, early diagnosis, and treatment, cancer morbidity and mortality has not been decreased during last forty years. Especially, lung cancer is top-ranked in cancer-associated human death. Therefore, effective strategy is strongly required for the management of lung cancer. In the present study, we found that novel daphnane diterpenoids, yuanhualine (YL), yuanhuahine (YH) and yuanhuagine (YG) isolated from the flower of Daphne genkwa (Thymelaeaceae), exhibited potent anti-proliferative activities against human lung A549 cells with the $IC_{50}$ values of 7.0, 15.2 and 24.7 nM, respectively. Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells. The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A, cyclin B1, cyclin E, cyclin dependent kinase 4, cdc2, phosphorylation of Rb and cMyc expression. In the analysis of signal transduction molecules, the daphnane diterpenoids suppressed the activation of Akt, STAT3 and Src in human lung cancer cells. The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549, gefitinib-, erlotinib-resistant H292 cells. Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine, gefitinib or erlotinib in A549 cells. Taken together, these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers.

• BMB Reports
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• v.48 no.3
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• pp.127-128
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• 2015

Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Hepatic TM4SF5 promotes EMT for malignant growth and migration. Hepatocellular carcinoma (HCC) biomarkers remain unexplored for metastatic potential throughout metastasis. Here, novel TM4SF5/CD44 interaction-mediated self-renewal and circulating tumor cell (CTC) capacities were mechanistically explored. TM4SF5-dependent sphere growth was correlated with $CD133^+$, $CD24^-$, ALDH activity, and a physical association between CD44 and TM4SF5. The TM4SF5/CD44 interaction activated c-Src/STAT3/ Twist1/ B mi1 signaling for spheroid formation, while disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts of less than 5,000 cells/injection, TM4SF5-positive tumors exhibited locally-increased CD44 expression, suggesting tumor cell differentiation. TM4SF5-positive cells were identified circulating in blood 4 to 6 weeks after orthotopic liver-injection. Anti-TM4SF reagents blocked their metastasis to distal intestinal organs. Altogether, our results provide evidence that TM4SF5 promotes self-renewal and CTC properties supported by $CD133^+/TM4SF5^+/CD44^+^{(TM4SF5-bound)}/ALDH^+/CD24^-$ markers during HCC metastasis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.38 no.1
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• pp.10-15
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• 2024

Previous studies have highlighted the pivotal role of the β-adrenergic receptor (β-AR) signaling pathway in stimulating cancer metastasis induced by chronic stress. According to the theory of traditional Korean medicine, chronic stress can induce Qi stagnation. Based on the traditional role of premature citrus unshiu peel in moving Qi, we hypothesized that an ethanol extract of premature citrus unshiu peel (EPCU) can attenuate chronic stress-induced cancer progression. In this study, we investigated the potential role of EPCU on modulating the adrenergic agonists-induced metastatic properties of liver cancer cells. Our findings revealed that adrenergic agonists, including norepinephrine (NE), epinephrine (E), and isoproterenol (ISO), augmented the migratory capacity of Hep3B human hepatocellular carcinoma cells, which was completely abrogated by EPCU treatment in a concentration-dependent manner. Consistently, EPCU inhibited the E-induced invasive property of Hep3B cells in a dose-dependent manner. These results suggest that EPCU efficiently attenuates adrenergic agonists-induced metastatic abilities of liver cancer cells. As a molecular mechanism, EPF suppressed the phosphorylation of major components of β-AR signaling pathway, including Src, signal transducer and activator of transcription 3 (STAT3) and ERK, induced by E treatment. Taken together, our results demonstrate that EPCU impedes the adrenergic agonists-driven metastatic potential of cancer cells by inhibiting β-AR signaling pathway. This study provides basic evidence supporting the probable use of premature citrus unshiu peel to prevent metastasis in liver cancer patients under chronic stress.