• Journal of Gastric Cancer
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• v.21 no.4
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• pp.439-456
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• 2021

Purpose: Gastric cancer (GC) has high morbidity and mortality and is a serious threat to public health. The flavonoid compound vitexin is known to exhibit anti-tumor activity. In this study, we explored the therapeutic potential of vitexin in GC and its underlying mechanism. Materials and Methods: The viability, migration, and invasion of GC cells were determined using MTT, scratch wound healing, and transwell assays, respectively. Target molecule expression was determined by western blotting. Tumor growth and liver metastasis were evaluated in vivo using nude mice. Protein expression in the tumor tissues was examined by immunohistochemistry. Results: Vitexin inhibited GC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) in a dose-dependent manner. Vitexin treatment led to the inactivation of phosphatidylinositol-3-kinase (PI3K)/AKT/hypoxia-inducible factor-1α (HIF-1α) pathway by repressing HMGB1 expression. Vitexin-mediated inhibition in proliferation, migration, invasion and EMT of GC cells were counteracted by hyper-activation of PI3K/AKT/HIF-1α pathway or HMGB1 overexpression. Finally, vitexin inhibited the xenograft tumor growth and liver metastasis in vivo by suppressing HMGB1 expression. Conclusions: Vitexin inhibited the malignant progression of GC in vitro and in vivo by suppressing HMGB1-mediated activation of PI3K/Akt/HIF-1α signaling pathway. Thus, vitexin may serve as a promising therapeutic agent for the treatment of GC.

• Molecules and Cells
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• v.44 no.11
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• pp.784-794
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• 2021

Leiomyosarcoma (LMS) is a mesenchymal malignancy with a complex karyotype. Despite accumulated evidence, the factors contributing to the development of LMS are unclear. Here, we investigated the role of tight-junction protein 1 (TJP1), a membrane-associated intercellular barrier protein during the development of LMS and the tumor microenvironment. We orthotopically transplanted SK-LMS-1 cells and their derivatives in terms of TJP1 expression by intramuscular injection, such as SK-LMS-1 Sh-Control cells and SK-LMS-1 Sh-TJP1. We observed robust tumor growth in mice transplanted with LMS cell lines expressing TJP1 while no tumor mass was found in mice transplanted with SK-LMS-1 Sh-TJP1 cells with silenced TJP1 expression. Tissues from mice were stained and further analyzed to clarify the effects of TJP1 expression on tumor development and the tumor microenvironment. To identify the TJP1-dependent factors important in the development of LMS, genes with altered expression were selected in SK-LMS-1 cells such as cyclinD1, CSF1 and so on. The top 10% of highly expressed genes in LMS tissues were obtained from public databases. Further analysis revealed two clusters related to cell proliferation and the tumor microenvironment. Furthermore, integrated analyses of the gene expression networks revealed correlations among TJP1, CSF1 and CTLA4 at the mRNA level, suggesting a possible role for TJP1 in the immune environment. Taken together, these results imply that TJP1 contributes to the development of sarcoma by proliferation through modulating cell-cell aggregation and communication through cytokines in the tumor microenvironment and might be a beneficial therapeutic target.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.368-379
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• 2022

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

• Journal of Gastric Cancer
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• v.22 no.4
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• pp.408-417
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• 2022

Purpose: Treatment options are limited after the failure of first-and second-line treatments in patients with HER2⁺ metastatic gastric cancer (mGC). The present study aimed to explore the efficacy, safety, and prognostic factors of apatinib efficacy as a third-line therapy for patients with human epithelial growth factor receptor 2-positive (HER2⁺) mGC. Materials and Methods: A total of 59 HER2⁺ mGC patients who received apatinib as third-line therapy were retrospectively enrolled in this two-center, single-arm, cohort study; the clinical response, survival data, and adverse events were retrieved. Results: The median progression-free survival (PFS) was 5.2 months (95% confidence interval [CI], 3.9-6.5), and the median overall survival (OS) was 8.2 months (95% CI, 6.6-9.8) Furthermore, forward stepwise multivariate Cox regression analysis showed that a higher Eastern Cooperative Oncology Group performance status score and multiple metastases were independently correlated with decreased PFS and OS (both P<0.05). The main adverse events were leukopenia (45.8%), hypertension (44.1%), thrombocytopenia (39.0%), hand-foot syndrome (37.3%), and elevated transaminase (33.9%). Grade 3 adverse events mainly included hypertension (5.1%) and neutropenia (5.1%); grade 4 adverse events did not occur. Conclusions: Apatinib is efficient and well tolerated in patients with HER2⁺ mGC as a third-line treatment, suggesting that it may be a candidate of choice for these patients.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.3
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• pp.241-256
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• 2023

Although chimeric antigen receptor T cell (CAR-T) is a promising immunotherapy in hematological malignancies, there remain many obstacles to CART cell therapy for solid tumors. Identifying appropriate tumor-associated antigens (TAAs) is especially critical for success. Using a bioinformatics approach, we identified common potential TAAs for CAR-T cell immunotherapy in solid tumors. We used the GEO database as a training dataset to find differentially expressed genes (DEGs) and verified candidates using the TCGA database, obtaining seven common DEGs (HM13, SDC1, MST1R, HMMR, MIF, CD24, and PDIA4). Then, we used MERAV to analyze the expression of six genes in normal tissues to determine the ideal target genes. Finally, we analyzed tumor microenvironment factors. The results of major microenvironment factor analyses showed that MDSCs, CXCL1, CXCL12, CXCL5, CCL2, CCL5, TGF- β, CTLA-4, and IFN-γ were significantly overexpressed in breast cancer. The expression of MST1R was positively correlated with TGF- β, CTLA-4, and IFN-γ. In lung adenocarcinoma, MDSCs, Tregs, CXCL12, CXCL5, CCL2, PD-L1, CTLA-4, and IFN-γ were significantly overexpressed in tumor tissues. The expression of MST1R was positively correlated with TGF- β, CTLA-4, and IFN-γ. In bladder cancer, CXCL12, CCL2, and CXCL5 were significantly overexpressed in tumor tissues. MST1R expression was positively correlated with TGF- β. Our results demonstrate that MST1R has the potential as a new target antigen for treating breast cancer, lung adenocarcinoma, and bladder cancer and may be used as a progression indicator for bladder cancer.

• BMB Reports
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• v.56 no.2
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• pp.120-125
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• 2023

Karyopherin-α3 (KPNA3), a karyopherin-α isoform, is intimately associated with metastatic progression via epithelial-mesenchymal transition (EMT). However, the molecular mechanism underlying how KPNA3 acts as an EMT inducer remains to be elucidated. In this report, we identified that KPNA3 was significantly upregulated in cancer cells, particularly in triple-negative breast cancer, and its knockdown resulted in the suppression of cell proliferation and metastasis. The comprehensive transcriptome analysis from KPNA3 knockdown cells indicated that KPNA3 is involved in the regulation of numerous EMT-related genes, including the downregulation of GATA3 and E-cadherin and the up-regulation of HAS2. Moreover, it was found that KPNA3 EMT-mediated metastasis can be achieved by TGF-β or AKT signaling pathways; this suggests that the novel independent signaling pathways KPNA3-TGF-β-GATA3-HAS2/E-cadherin and KPNA3-AKT-HAS2/E-cadherin are involved in the EMT-mediated progress of TNBC MDA-MB-231 cells. These findings provide new insights into the divergent EMT inducibility of KPNA3 according to cell and cancer type.

• Genomics & Informatics
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• v.21 no.1
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• pp.8.1-8.19
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• 2023

Cancer of the stomach is the second most frequent cancer-related death worldwide. The survival rate of patients with gastric cancer (GC) remains fragile. There is a requirement to discover biomarkers for prognosis approaches. Helicobacter pylori in the stomach is closely associated with the progression of GC. We identified the genes associated with poor/favorable prognosis in H. pylori-induced GC. Multivariate statistical analysis was applied on the Gene Expression Omnibus (GEO) dataset GSE54397 to identify differentially expressed miRNAs (DEMs) in gastric tissues with H. pylori-induced cancer compared with the H. pylori-positive with non-cancerous tissue. A protein interaction map (PIM) was built and subjected to DEMs targets. The enriched pathways and biological processes within the PIM were identified based on substantial clusters. Thereafter, the most critical genes in the PIM were illustrated, and their prognostic impact in GC was investigated. Considering p-value less than 0.01 and |Log2 fold change| as >1, five microRNAs demonstrated significant changes among the two groups. Gene functional analysis revealed that the ubiquitination system, neddylation pathway, and ciliary process are primarily involved in H. pylori-induced GC. Survival analysis illustrated that the overexpression of DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, and TXNIP was associated with poor prognosis, while increased MRPS5 expression was related to a favorable prognosis in GC patients. DOCK4, GNAS, CTGF, TGF-b1, ESR1, SELE, TIMP3, SMARCE1, TXNIP, and MRPS5 may be considered prognostic biomarkers for H. pylori-induced GC. However, experimental validation is necessary in the future.

• Journal of Digestive Cancer Research
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• v.6 no.2
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• pp.73-77
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• 2018

A 70-year-old female diagnosed with pancreatic ductal adenocarcinoma was treated by pylorus-preserving pancreaticoduodenectomy (PPPD) and adjuvant concurrent chemoradiotherapy with 5-fluorouracil. Pancreatic ductal adenocarcinoma pT3N0 (stage IIA) was pathologically confirmed. Abdominal computed tomography (CT) findings 14 months after PPPD showed 10 mm sized solitary liver metastasis in segment 3. After 12 cycles of gemcitabine and 9 cycles of capecitabine plus oxaliplatin, the metastatic nodule increased in size to 27 mm. Tumorectomy at segment 3 of liver was done. 25 months after tumorectomy, chest CT showed 23 mm sized cavitary nodule in right upper lobe of lung. The result of percutaneous biopsy favored metastatic adenocarcinoma. Two sets of stereotactic body radiation therapy were done and the patient has survived without further disease progression for 6 years after initial diagnosis. This case suggests that selected population of recurrent pancreatic cancer patients with solitary liver or pulmonary metastasis can be treated by resection of metastatic site and ablative therapies.

• Journal of Digestive Cancer Research
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• v.5 no.1
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• pp.62-65
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• 2017

Pancreatic cancer is an aggressive disease and despite the efforts of the past few decades, the 5-year overall survival (OS) rate remains disappointing and does not exceed 10% in Korea. Especially, only 15-20% of patients are candidates for surgical resection because most patients are diagnosed with locally advanced or metastatic disease, and their only treatment approach is palliative chemotherapy. Since the first chemo-regimen of Gemcitabine and Nanoparticle albumin bound (nab) - paclitaxel was brought to clinical practice in 2013, the improvement in overall survival, progression-free survival, and response rate was achieved in patients with metastatic pancreatic adenocarcinoma. We report the case of a young patient with cardiogenic shock accompanied by multi-organ failure after 4^th cycle Gemcitabine and nab-paclitaxel chemotherapy with partial response.

• Journal of Genetic Medicine
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• v.20 no.2
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• pp.52-59
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• 2023

Purpose: Colorectal cancer (CRC) is a common malignancy worldwide and the second leading cause of cancer-related deaths. In addition, lymph node metastasis in CRC is considered an important prognostic factor for predicting disease recurrence and patient survival. Recent studies demonstrated that the microbiome makes substantial contributions to tumor progression, however, there is still unknown about the microbiome associated with lymph node metastasis of CRC. Here, we first reported the microbial and tumor-infiltrating immune cell differences in CRC according to the lymph node metastasis status. Materials and Methods: Using Next Generation Sequencing data acquired from 368 individuals diagnosed with CRC (N0, 266; N1, 102), we applied the LEfSe to elucidate microbial differences. Subsequent utilization of the Kaplan-Meier survival analysis enabled the identification of particular genera exerting significant influence on patient survival outcomes. Results: We found 18 genera in the N1 group and 3 genera in the N0 group according to CRC lymph node metastasis stages. In addition, we found that the genera Crenobacter (P=0.046), Maricaulis (P=0.093), and Arsenicicoccus (P=0.035) in the N0 group and Cecembia (P=0.08) and Asanoa (P=0.088) in the N1 group were significantly associated with patient survival according to CRC lymph node metastasis stages. Further, Cecembia is highly correlated to tumor-infiltrating immune cells in lymph node metastasized CRC. Concolusion: Our study highlights that tumor-infiltrating immune cells and intratumoral microbe diversity are associated with CRC. Also, this potential microbiome-based oncology diagnostic tool warrants further exploration.