• 생명과학회지
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• 제31권10호
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• pp.873-884
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• 2021

본 연구에서는 다양한 인체 암포주를 대상으로 NSAID의 항암 효과를 증강시키는 artesunate (ART)의 역할과 이에 대한 분자적 기전을 연구하였다. 다양한 타입의 암세포주를 대상으로 암세포 성장 억제 활성을 조사한 결과, ART는 NSAID인 celecoxib (CCB) 또는 dimethyl-CCB (DMC)와의 병용 효과를 나타내었다. ART 처리로 ATF4/CHOP의 발현 증강과 함께 오토파지 유도 표식인 p62 감소의 결과로서, ATF4/CHOP 경로가 ART의 오토파지 유도 활성에 관여할 것으로 예상되었으며, ART의 오토파지 활성과 관련하여 NRF2 및 암 줄기 세포 관련 단백질인 CD44, CD133, ALDH1, Oct4, mutated p53 (mutp53) 및 c-Myc의 발현이 감소되었다. 또한 DMC 단독처리 보다 ART와 DMC의 병용으로 ATF4/CHOP의 발현 증강과 p62의 감소가 더욱 촉진되고, NRF2 및 암 줄기 세포 관련 단백질 발현 감소도 현저히 촉진되면서 궁극적으로 PARP 활성화에 의해 apoptosis가 유도됨을 알 수 있었다. 이러한 결과는 ART/DMC 병용 처리가 각 물질 단독 처리보다 암세포의 성장 억제 및 apoptosis 유도에 더욱 효과적이고, ART 및 DMC 의 오토파지 유도 활성은 암 줄기 세포 관련 단백질의 분해를 촉진함으로써, 암 줄기 세포가 제거될 수 있음을 시사하였다. 이와 같이 ART는 NSAID 뿐만 아니라 imatinib의 항암 효과를 증강시키는 활성으로, chemosensitizer로서 중요한 후보 물질이 될 수 있음을 밝혔다.

• 생명과학회지
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• 제32권3호
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• pp.210-221
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• 2022

비스테로이드소염제(NSAID)와 γ-secretase 저해제(DAPT) 또는 SIRT1저해제(MHY2245)의 병용 효과를 인간 대장암(KM12) 및 간암(SNU475) 세포를 대상으로 조사한 결과, celecoxib (CCB) 및 2, 5-dimethyl celecoxib (DMC)를 포함하는 NSAID는 DAPT 또는 MHY2245와의 병용에 의하여 COX-2활성과 상관없이 NSAID의 암세포 증식 억제능이 현저히 증강되었다. DAPT와 MHY2245는 p62단백질 감소와 동시에 Notch1, CD44, CD133, octamer- binding transcription factor 4 (Oct4) 등의 다수의 종양 줄기세포 표지자 및 NICD1 발현 양을 감소시켰지만, activating transcription factor 4 (ATF4) 발현은 증강시켰다. 또한 NSAID 단독처리 보다 NSAID/DAPT 및 NSAID/MHY2245 병용 처리에 의하여 오토파지가 촉진되므로서 종양 줄기세포 표지자의 발현 및 단백질양의 감소가 가속화되고, 이에 따라 PARP 활성화 및 세포사멸이 현저히 증강 되었다. 결론적으로 NSAID/DAPT 및 NSAID/MHY2245의 병용 투여는 종양 줄기세포 표지자를 발현하는 인간 암세포의 증식 억제 및 제거에 효과적인 처리방법으로, 임상에 적용시킬 수 있는 학문적 근거로서 제공 될 수 있다.

• International Journal of Oral Biology
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• 제37권4호
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• pp.175-180
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• 2012

Skin-derived precursor cells (SKPs) are multipotent, sphere-forming and embryonic neural crest-related precursor cells that can be isolated from dermis. It is known that the properties of porcine SKPs can be enhanced by leukemia inhibitory factor (LIF) which is an essential factor for the generation of embryonic stem cells in mice. In our present study, to enhance or maintain the properties of murine SKPs, LIF was added to the culture medium. SKPs were treated with 1,000 IU LIF for 72 hours after passage 3. Quantitative real time RT-PCR was then performed to quantify the expression of the pluripotent stem cell specific genes Oct4, Nanog, Klf4 and c-Myc, and the neural crest specific genes Snai2 and Ngfr. The results show that the expression of Oct4 is increased in murine SKPs by LIF treatment whereas the level of Ngfr is decreased under these conditions. Interestingly, LIF treatment reduced Nanog expression which is also important for cell proliferation in adult stem cells and for osteogenic induction in mesenchymal stem cells. These findings implicate LIF in the maintenance of stemness in SKPs through the suppression of lineage differentiation and in part through the control of cell proliferation.

• Molecules and Cells
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• 제38권3호
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• pp.202-209
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• 2015

Hepatocellular carcinoma (HCC), a highly malignant disease and the third leading cause of all cancer mortalities worldwide, often responses poorly to current treatments and results in dismal outcomes due to frequent chemoresistance and tumor relapse. The heterogeneity of HCC is an important attribute of the disease. It is the outcome of many factors, including the cross-talk between tumor cells within the tumor microenvironment and the acquisition and accumulation of genetic and epigenetic alterations in tumor cells. In addition, there is accumulating evidence in recent years to show that the malignancy of HCC can be attributed partly to the presence of cancer stem cell (CSC). CSCs are capable to self-renew, differentiate and initiate tumor formation. The regulation of the stem cell-like properties by several important signaling pathways have been found to endow the tumor cells with an increased level of tumorigenicity, chemoresistance, and metastatic ability. In this review, we will discuss the recent findings on hepatic CSCs, with special emphasis on their putative origins, relationship with hepatitis viruses, regulatory signaling networks, tumor microenvironment, and how these factors control the stemness of hepatic CSCs. We will also discuss some novel therapeutic strategies targeted at hepatic CSCs for combating HCC and perspectives of future investigation.

• 한국수정란이식학회지
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• 제27권3호
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• pp.171-174
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• 2012

Various small molecules can be used to control major signaling pathways to enhance stemness and inhibit differentiation in murine embryonic stem cell (mESC) culture. Small molecules inhibiting the fibroblast growth factor (FGF)/ERK pathway can preserve pluripotent cells from stimulation of differentiation. In this study, we aimed to evaluate the effect of pluripotin (SC-1), an inhibitor of the FGF/ERK pathway, on the colony formation of outgrowing presumptive mESCs. After plating the zona pellucida-free blastocyst on the feeder layer, attached cell clumps was cultured with SC-1 until the endpoint of the experiment at passage 10. In this experiment, when the number of colonies was counted at passage 3, SC-1-treated group showed 3.4 fold more mESC colonies when compared with control group. However, after passage 4, there was no stimulating effect of SC-1 on the colony formation. In conclusion, SC-1 treatment can be used to promote mESC generation by increasing the number of early mESC colonies.

• BMB Reports
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• 제48권10호
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• pp.539-540
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• 2015

It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer.

• Molecules and Cells
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• 제42권2호
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• pp.175-182
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• 2019

microRNAs regulate a diverse spectrum of cancer biology, including tumorigenesis, metastasis, stemness, and drug resistance. To investigate miRNA-mediated regulation of drug resistance, we characterized the resistant cell lines to 5-fluorouracil by inducing stable expression of miRNAs using lenti-miRNA library. Here, we demonstrate miR-551a as a novel factor regulating cell survival after 5-FU treatment. miR-551a-expressing cells (Hep3B-lenti-miR-551a) were resistant to 5-FU-induced cell death, and after 5-FU treatment, and showed significant increases in cell viability, cell survival, and sphere formation. It was further shown that myocyte-specific factor 2C is the direct target of miR-551a. Our results suggest that miR-551a plays a novel function in regulating 5-FU-induced cell death, and targeting miR-551a might be helpful to sensitize cells to anti-cancer drugs.

• International Journal of Oral Biology
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• 제45권4호
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• pp.197-203
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• 2020

Mesenchymal stem cells in the dental pulp exhibit a tendency for differentiation into various dental lineages and hold great potential as a major conduit for regenerative treatment in dentistry. Although they can be readily isolated from teeth, the exact characteristics of these stem cells have not been fully understood so far. When compared to two-dimensional (2D) cultures, three-dimensional (3D) cultures have the advantage of enriching the stem cell population. Hence, 3D-organoid culture and 3D-sphere culture were applied to dental pulp cells in the current study. Although the establishment of the organoid culture proved unsuccessful, the 3D-sphere culture readily initiated the stable generation of cell aggregates, which continued to grow and could be passaged to the second round. Interestingly, a significant increase in SOX2 expression was detected in the 3D-spheroid culture compared to the 2D culture. These results indicate the enrichment of the stemness-high population in the 3D-sphere culture. Thus, 3D-sphere culture may act as a link between the conventional and 3D-organoid cultures and aid in understanding the characteristics of dental pulp stem cells.

• Molecules and Cells
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• 제45권9호
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• pp.610-619
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• 2022

Cellular senescence plays a paradoxical role in tumorigenesis through the expression of diverse senescence-associated (SA) secretory phenotypes (SASPs). The heterogeneity of SA gene expression in cancer cells not only promotes cancer stemness but also protects these cells from chemotherapy. Despite the potential correlation between cancer and SA biomarkers, many transcriptional changes across distinct cell populations remain largely unknown. During the past decade, single-cell RNA sequencing (scRNA-seq) technologies have emerged as powerful experimental and analytical tools to dissect such diverse senescence-derived transcriptional changes. Here, we review the recent sequencing efforts that successfully characterized scRNA-seq data obtained from diverse cancer cells and elucidated the role of senescent cells in tumor malignancy. We further highlight the functional implications of SA genes expressed specifically in cancer and stromal cell populations in the tumor microenvironment. Translational research leveraging scRNA-seq profiling of SA genes will facilitate the identification of novel expression patterns underlying cancer susceptibility, providing new therapeutic opportunities in the era of precision medicine.

• BMB Reports
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• 제56권4호
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• pp.252-257
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• 2023

The hypoxia-inducible factor-1α (HIF-1α) is a key regulator of hypoxic stress under physiological and pathological conditions. HIF-1α protein stability is tightly regulated by the ubiquitin-proteasome system (UPS) and autophagy in normoxia, hypoxia, and the tumor environment to mediate the hypoxic response. However, the mechanisms of how the UPS and autophagy interplay for HIF-1α proteostasis remain unclear. Here, we found a HIF-1α species propionylated at lysine (K) 709 by p300/CREB binding protein (CBP). HIF-1α stability and the choice of degradation pathway were affected by HIF-1α propionylation. K709-propionylation prevented HIF-1α from degradation through the UPS, while activated chaperon-mediated autophagy (CMA) induced the degradation of propionylated and nonpropionylated HIF-1α. CMA contributed to HIF-1α degradation in both normoxia and hypoxia. Furthermore, the pan-cancer analysis showed that CMA had a significant positive correlation with the hypoxic signatures, whereas SIRT1, responsible for K709-depropionylation correlated negatively with them. Altogether, our results revealed a novel mechanism of HIF-1α distribution into two different degradation pathways.