• Journal of Ginseng Research
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• 제43권3호
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• pp.421-430
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• 2019

Background: The ginsenoside Rg3, one of active components of red ginseng, has chemopreventive and anticancer potential. Cancer stem cells retain self-renewal properties which account for cancer recurrence and resistance to anticancer therapy. In our present study, we investigated whether the standardized Korean Red Ginseng extract (RGE) and Rg3 could modulate the manifestation of breast cancer stem cell-like features through regulation of self-renewal activity. Methods: The effects of RGE and Rg3 on the proportion of $CD44^{high}/CD24^{low}$ cells, as representative characteristics of stem-like breast cancer cells, were determined by flow cytometry. The mammosphere formation assay was performed to assess self-renewal capacities of breast cancer cells. Aldehyde dehydrogenase activity of MCF-7 mammospheres was measured by the ALDEFLUOR assay. The expression levels of Sox-2, Bmi-1, and P-Akt and the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres were verified by immunoblot analysis. Results: Both RGE and Rg3 decreased the viability of breast cancer cells and significantly reduced the populations of $CD44^{high}/CD24^{low}$ in MDA-MB-231 cells. RGE and Rg3 treatment attenuated the expression of Sox-2 and Bmi-1 by inhibiting the nuclear localization of hypoxia inducible $factor-1{\alpha}$ in MCF-7 mammospheres. Suppression of the manifestation of breast cancer stem cell-like properties by Rg3 was mediated through the blockade of Akt-mediated self-renewal signaling. Conclusion: This study suggests that Rg3 has a therapeutic potential targeting breast cancer stem cells.

• Molecules and Cells
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• 제44권1호
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• pp.50-62
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• 2021

Among all cancer types, lung cancer ranks highest worldwide in terms of both incidence and mortality. The crosstalk between lung cancer cells and their tumor microenvironment (TME) has begun to emerge as the "Achilles heel" of the disease and thus constitutes an attractive target for anticancer therapy. We previously revealed that crosstalk between lung cancer cells and endothelial cells (ECs) induces chemoresistance in multicellular tumor spheroids (MCTSs). In this study, we demonstrated that factors secreted in response to crosstalk between ECs and lung cancer cells play pivotal roles in the development of chemoresistance in lung cancer spheroids. We subsequently determined that the expression of hypoxia up-regulated protein 1 (HYOU1) in lung cancer spheroids was increased by factors secreted in response to crosstalk between ECs and lung cancer cells. Direct interaction between lung cancer cells and ECs also caused an elevation in the expression of HYOU1 in MCTSs. Inhibition of HYOU1 expression not only suppressed stemness and malignancy, but also facilitated apoptosis and chemosensitivity in lung cancer MCTSs. Inhibition of HYOU1 expression also significantly increased the expression of interferon signaling components in lung cancer cells. Moreover, the activation of the PI3K/AKT/mTOR pathway was involved in the HYOU1-induced aggression of lung cancer cells. Taken together, our results identify HYOU1, which is induced in response to crosstalk between ECs and lung cancer cells within the TME, as a potential therapeutic target for combating the aggressive behavior of cancer cells.

• Journal of Gastric Cancer
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• 제21권4호
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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.

• Asian Pacific Journal of Cancer Prevention
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• 제15권14호
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• pp.5819-5823
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• 2014

Purpose: To investigate the expression of hypoxia-inducible factor prolyl hydroxylase 3 (HIFPH3) in non-small cell lung cancer (NSCLC) and explore the correlation of HIFPH3 expression with lymph node metastasis and microvessel density (MVD). Materials and Methods: A total of 73 cases of NSCLC specimens, 24 cases of para-cancerous tissues, and 20 normal pulmonary tissues were collected for HIFPH3 and CD31 immunohistochmical (IHC) study. Microvessel density (MVD) of the NSCLC tissues was also determined based on the expression of CD31. Results: The expression of HIFPH3 in carcinoma tissue was statistically higher than para-cancerous and normal pulmonary tissues (${\chi}^2=48.806$, p<0.05). Compared withthe negative lymph node metastasis group, the lymph node metastasis group showed significantly higher HIFPH3 expression (${\chi}^2=6.300$, p<0.05). The strong HIFPH3+group displayed a significantly higher MVD than weak HIFPH3+ and HIFPH3- groups (p<0.05). No differences in positive HIFPH3 expression were noted regarding the tumor diameter, age, smoking status, gender of NSCLC patients, tumor size, histopathology, or differentiation. Conclusions: HIFPH3 expression in human NSCLC lesions is significantly higher than that in para-cancerous and normal lung tissues and is positively associated with lymph node metastasis and MVD.

• BMB Reports
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• 제54권7호
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• pp.344-355
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• 2021

Mucins are high molecular-weight epithelial glycoproteins and are implicated in many physiological processes, including epithelial cell protection, signaling transduction, and tissue homeostasis. Abnormality of mucus expression and structure contributes to biological properties related to human cancer progression. Tumor growth sites induce inhospitable conditions. Many kinds of research suggest that mucins provide a microenvironment to avoid hypoxia, acidic, and other biological conditions that promote cancer progression. Given that the mucus layer captures growth factors or cytokines, we propose that mucin helps to ameliorate inhospitable conditions in tumor-growing sites. Additionally, the composition and structure of mucins enable them to mimic the surface of normal epithelial cells, allowing tumor cells to escape from immune surveillance. Indeed, human cancers such as mucinous carcinoma, show a higher incidence of invasion to adjacent organs and lymph node metastasis than do non-mucinous carcinoma. In this mini-review, we discuss how mucin provides a tumor-friendly environment and contributes to increased cancer malignancy in mucinous carcinoma.

• Genomics & Informatics
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• 제6권2호
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• pp.72-76
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• 2008

Hypoxia-inducible factor $1{\alpha}\;(HIF1{\alpha})$ is a transcription factor that plays a key role in the adaptation of cells to low oxygen stress and oxygen homeostasis. The oxygen-dependent degradation (ODD) domain of $HIF1{\alpha}$ is responsible for the negative regulation of $HIF1{\alpha}$ in normoxia. The interactions of the $HIF1{\alpha}$ ODD domain with partner proteins such as von Hippel-Lindau tumor suppressor (pVHL) and p53 are mediated by two sequence motifs, the N- and C-terminal ODD(NODD and CODD). Multiple sequence alignment with $HIF1{\alpha}$ homologs from human, monkey, pig, rat, mouse, chicken, frog, and zebrafish has demonstrated that the NODD and CODD motifs have noticeably high conservation of the primary sequence across different species and isoforms. In this study, we carried out molecular dynamics simulation of the structure of the $HIF1{\alpha}$ CODD motif in complex with the p53 DNA-binding domain (DBD). The structure reveals specific functional roles of highly conserved residues in the CODD sequence motif of $HIF1{\alpha}$ for the recognition of p53.

• 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.

• Radiation Oncology Journal
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• 제18권2호
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• pp.120-126
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• 2000

목적 : 종양내 저산소상태는 저산소세포치사제에 의하여 극복이 가능하다. 방사선의 반응을 증강시키는 tirapazamine 의 효과가 마우스 종양에서 분할방사선조사와 병용된 상태에서 종양내 산소상태에 따라 어떠한 영향을 받는가를 확인하고자 하였다. 대상 및 방법 : 대조군 및 저산소 상태의 종양을 수립하기 위하여 정상 및 4주전에 방사선 조사를 받았던 마우스의 등과 하지에 RIF-1 종양을 이식하였다. 종양이 일정한 크기에 도달하면, 대조군 및 저산소 상태 종양에 대하여 생리식염수(0.02 mlg), tirapazamine (0.08 mMkg), 방사선조사(2.5 Gy), tirapazamine 과 방사선조사의 병용 등을 사용하여 4일간 8회의 과분할 치료를 시행하였다. 등의 종양 체적이 4 배로 증가하거나 하지의 종양 단면이 2배로 증가할 때 까지 종양의 크기 변화를 측정하여 얻은 종양성장의 지연을 기준으로 각 치료에 대한 반응을 평가하였다. 결과 : 등 및 하지의 정상 및 저산소종양의 평균증식양상으로 부터 tirapazamine이 방사선의 반응을 증강시켰음을 알 수 있다. tirapazamine에 의한 방사선증강효과는 호기의 종양체적 또는 종양단면적을 기준으로 한 증식지연실험 결과 등의 정상종양에서는 1.9배, 저산소종양에서는 2.4배였으며 하지의 정상종양에서는 1.85배, 저산소종양에서는 1.6배였다. 초기종양체적의 4배 증식 또는 종양단면적의 2배 증식까지의 기간을 기준으로 설정한 증식지연실험결과 등의 정상종양에서는 1.48배, 저산소종양에서는 2.0배였으며 하지의 정상종양에서는 1.85배, 저산소종양에서는 1.6배였다. 결론 :분할 방사선조사에 tirapazamine을 병용할 경우 방사선조사효과는 증강되며, 저산소상태에 있는 마우스 종양에서의 증강효과가 대조 종양에서의 증강효과와 동일하거나 더욱 양호할 가능성을 제시할 수 있었다.었으나 $7.4\%$만이 심한 증상을 보였고, 만성 합병증은 $7.9\%$에서 관찰되었으며, 장폐색, 비뇨기계증상의 악화, 방사선 방광염등의 순이었다.전에 예방하기 위해 중점 관리해야 할 지점에 대해 더 많은 정보를 얻을 수 있으리라고 사료된다.이었고(p<0.01) 포장에 대해서는 주택형태에 따라 농가나 아파트에 거주하는 주부가 단독주택이나 연립주택에 거주하는 주부보다 더 나쁘게 평가하는 경향이었다. (p<0.05) (9) 조사대상주부들은 시판제품의 가장 개선해야 할 점으로 위생성(37.0%), 가격(23.8%), 포장(15.6%), 맛(11.1%), 저장성(10.1%) 및 색(2.4%) 등의 순으로 지적하였고 주부의 거주지에 따라 대도시에 거주할수록 위생성을, 농어촌에 거주할수록 가격을 가장 개선해야 할 점으로 보는 경향이었다. (p<0.05)3.2%는 채소에는 cholesterol이 함유되어 있지 않으므로 채식이 건강에 좋다고 하였다. 또한 질병치료에 유효한 채소는 당근 등 42가지, 질병을 유발시키는 채소는 고사리 등 10종을 지적하였으며 이들은 과학적 증명이 가능하거나 민간요법으로 전해지고 있는 내용이다. 이상과 같이 덕성여자대학교 평생교육원에 다니는 주부의 채소 소비 형태에 대하여 살펴보았는데 가공된 채소반찬과 김치의 구입은 현재까지 일반화되지 않고 있음을 알 수 있으나 김치보다 채소반찬의 구입경험이 더 많은 것으로 나타났다. 본 논문은 덕성여자대학교 평생교육원에 다니는 주부를 대상으로 하였으나 앞으로 다양한 계층의 주부를 대상으로 하여 폭 넓은 채소소비에 관련된 연구가 이루어져야 한다고 사료된다.할 경우 적정 첨가 수준으로 당화액과 추출액의 비가 3:7의 범위를 넘지 않아야 버섯의 장점을 살리면서 기존 조청의 특성을 변화시키지 않는 제품을 제조할 수 있을 것으로 보인다.mic acid의 생성량(生成量)

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3613-3618
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• 2013

Object: To detect expression of hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and lysyl oxidase (LOX) in non-small cell lung cancer (NSCLC) and explore their roles in prognosis. Methods: The mRNA levels of HIF-$1{\alpha}$ and LOX were investigated by real-time reverse-transcriptase polymerase chain reaction in 40 cases of tumour and paired normal tissues. In addition, protein expression of HIF-$1{\alpha}$ and LOX was examined by immunohistochemistry in 82 cases of tumour and 45 paired normal tissues. The relationship between HIF-$1{\alpha}$ or LOX and clinicopathologic characteristics, as well as the correlation between HIF-$1{\alpha}$ and LOX, were also examined. Kaplan-Meier survival curves and the log-rank test were used to analyze progression-free survival. Results: HIF-$1{\alpha}$ or LOX mRNA levels in tumor tissues was significantly higher than those in paired normal tissues (p<0.01). Positive HIF-$1{\alpha}$ or LOX protein expression in tumor tissues was noted in 46/82 (56.1%) and 49/82 (59.8%) of the cases, respectively, being significantly higher than those in paired normal tissues (p<0.05). There was significant correlation between the expression of HIF-$1{\alpha}$ or LOX and tumor size, lymph node metastasis and pathological stage (p<0.05). The expression of HIF-$1{\alpha}$ and LOX had a significant inverse impact on survival of patients with NSCLC. Conclusion: HIF-$1{\alpha}$ and LOX may play a pivotal role in the development of NSCLC, and may act in synergy to promote the progression of NSCLC.

• BMB Reports
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• 제40권3호
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• pp.439-443
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• 2007

Tumor growth and metastasis are dependent on angiogenesis, and endothelial cell invasion and migration are apparent means of regulating tumor progression. We report here that saxatilin, a snake venom-derived disintegrin, suppresses the angiogenesis-inducing properties of NCI-H460 human lung cancer cells. Culture supernatants of NCI-H460 cells are able to induce human umbilical vascular endothelial cell (HUVEC) invasion and tube formation. However, treatment of the cancer cells with saxatilin resulted in reduced angiogenic activity of the culture supernatant. This suppressed angiogenic property was found to be associated with the level of vascular endothelial growth factor (VEGF) in the culture supernatant. Further experimental evidence indicated that saxatilin inhibits VEGF production in NCI-H460 cells by affecting hypoxia induced factor-1$\alpha$ (HIF-1$\alpha$) expression via the Akt pathway.