• Biomolecules & Therapeutics
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• 제23권3호
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• pp.225-232
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• 2015

We identified a novel Akt signaling mechanism that mediates fucoidan-induced suppression of human colon cancer cell (HT29) proliferation and anticancer effects. Fucoidan treatment significantly inhibited growth, induced G1-phase-associated upregulation of p21WAF1 expression, and suppressed cyclin and cyclin-dependent kinase expression in HT29 colon cancer cells. Additionally, fucoidan treatment activated the Akt signaling pathway, which was inhibited by treatment with an Akt inhibitor. The inhibition of Akt activation reversed the fucoidan-induced decrease in cell proliferation, the induction of G1-phase-associated p21WAF1 expression, and the reduction in cell cycle regulatory protein expression. Intraperitoneal injection of fucoidan reduced tumor volume; this enhanced antitumor efficacy was associated with induction of apoptosis and decreased angiogenesis. These data suggest that the activation of Akt signaling is involved in the growth inhibition of colon cancer cells treated with fucoidan. Thus, fucoidan may serve as a potential therapeutic agent for colon cancer.

• Biomolecules & Therapeutics
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• 제26권3호
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• pp.313-321
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• 2018

Anti-cancer drug resistance is a major problem in colorectal cancer (CRC) research. Although several studies have revealed the mechanism of cancer drug resistance, molecular targets for chemotherapeutic combinations remain elusive. To address this issue, we focused on the expression of cellular prion protein ($PrP^C$) in 5-FU-resistant CRC cells. In 5-FU-resistant CRC cells, $PrP^C$ expression is significantly increased, compared with that in normal CRC cells. In the presence of 5-FU, $PrP^C$ increased CRC cell survival and proliferation by maintaining the activation of the PI3K-Akt signaling pathway and the expression of cell cycle-associated proteins, including cyclin E, CDK2, cyclin D1, and CDK4. In addition, $PrP^C$ inhibited the activation of the stress-associated proteins p38, JNK, and p53. Moreover, after treatment of 5-FU-resistant CRC cells with 5-FU, silencing of $PrP^C$ triggered apoptosis via the activation of caspase-3. These results indicate that $PrP^C$ plays a key role in CRC drug resistance. The novel strategy of combining chemotherapy with $PrP^C$ targeting may yield efficacious treatments of colorectal cancer.

• BMB Reports
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• 제56권10호
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• pp.557-562
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• 2023

Dysregulation of the E3 ubiquitin ligase Parkin has been linked to various human cancers, indicating that Parkin is a tumor suppressor protein. However, the mechanisms of action of Parkin remain unclear to date. Thus, we aimed to elucidate the mechanisms of action of Parkin as a tumor suppressor in human lung and colorectal cancer cells. Results showed that Parkin overexpression reduced the viability of A549 human lung cancer cells by inducing G2/M cell cycle arrest. In addition, Parkin caused DNA damage and ATM (Ataxia telangiectasia mutated) activation, which subsequently led to p53 activation. It also induced the p53-mediated upregulation of p21 and downregulation of cyclin B1. Moreover, Parkin suppressed the proliferation of HCT-15 human colorectal cancer cells by a mechanism similar to that in A549 lung cancer cells. Taken together, our results suggest that the tumor-suppressive effects of Parkin on lung and colorectal cancer cells are mediated by DNA damage/p53 activation/cyclin B1 reduction/cell cycle arrest.

• 핵의학기술
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• 제25권1호
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• pp.21-28
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• 2021

갈색지방세포(Brown fat 또는 Brown Adipose Tissue, BAT)는 포도당 대사(glucose metabolism)와 비오한성 열생성(non-shivering thermogenesis)을 통하여 열을 발산하여 추위로부터 생명체를 보호한다. BAT의 활성화는 연령, 성별, 체질량지수(BMI) 등의 환자 내적 요인과 기온, 환경 등의 환자외적 요인에 의해 확률적으로 발생한다. 본 연구에서는 후향적, 의무기록 관찰 연구를 진행하여 여러 인자들을 추출하고 통계 분석을 실시하여 BAT 활성화와 여러 인자 간에 관련성을 확인하고자 한다. 2018년 1월부터 2019년 12월까지 2년간 국립암센터에서 PET/CT 검사를 시행한 환자의 의무기록을 수집하여 총 9155명의 환자를 추출하고 중복 검사를 포함한 13442건의 환자데이터를 대상으로 하였다. 환자데이터의 의무기록에서는 BAT 발생여부, 성별, 검사당시 나이, 영상촬영날짜, 검사장소, 주사시간, 키, 체중, 혈당, 진단명이 나오도록 조건을 설정하였다. BAT 활성화가 PET/CT 촬영 시 환경(기온, 검사장소)과 환자의 상태(혈당, BMI, 암의 종류, 성별, 나이)에 따라 영향을 받는지 확인하기 위하여 단변량 로지스틱 회귀분석을 실행한 후, P<0.1인 변수를 선택하여 BAT 활성화에 영향을 주는 다변량 회귀분석 모형을 최종적으로 분석하였다. BAT 활성화는 전체 13442건 중 93건(0.7%)이 발생되었다. 단변수 로지스틱 회귀분석 결과에서 유의한 결과는, 50세 이상인 환자보다 50세 미만인 환자에게서(P<0.001), 여성이 남성에 비해서(P<0.001), 외부기온 14.5도 미만에서(P<0.001), 정상 BMI보다 낮은 BMI에서(P<0.001), 혈당이 100mg/dl 미만에서(P<0.001), 오후 12시 30분 이전에 주사를 맞은 환자에게서(P<0.001) BAT 활성화가 증가하였다. 반면, 정상보다 높은 BMI에서(P<0.001), 폐암진단을 받은 환자에게서(P<0.05) 감소하였다. 다변수 결과에서는, 50세 미만인 환자에게서(P<0.001), 여성에게서(P<0.001), 외부기온 14.5도 미만에서(P<0.001) BAT 활성화가 유의하게 증가하였고, 정상보다 높은 BMI에서(P<0.05) 유의하게 감소하였다. 국립암센터에서 2년간 PET/CT 시행한 환자를 대상으로 BAT 활성화에 영향을 미치는 인자에 대한 후행 연구를 진행하였다. 그 결과, 외부기온 14.5도 미만의 날씨에 PET/CT 검사를 시행했던 50대 미만의 정상 체중 여성에게서 BAT가 유의하게 활성화가 되었음을 확인할 수 있었다. 이 결과를 토대로 해당 인자에 적용된 환자를 사전에 식별할 수 있으며, 앞으로 여러 연구를 통하여 BAT의 활성화를 줄이는 것에 도움이 될 수 있다고 사료된다.

• Molecules and Cells
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• 제45권5호
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• pp.329-342
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• 2022

The liver is the predominant metastatic site for pancreatic cancer. However, the factors that determine the liver metastasis and the specific molecular mechanisms are still unclear. In this study, we used human pancreatic cancer cell line Hs766T to establish Hs766T-L3, a subline of Hs766T with stable liver metastatic ability. We performed RNA sequencing of Hs766T-L3 and its parental cell line Hs766T, and revealed huge differences in gene expression patterns and pathway activation between these two cell lines. We correlated the difference in pathway activation with the expression of the four core transcriptional factors including STAT1, NR2F2, GATA2, and SMAD4. Using the TCGA database, we examined the relative expression of these transcription factors (TFs) in pan-cancer and their relationship with the prognosis of the pancreatic cancer. Among these TFs, we considered GATA2 is closely involved in tumor metastasis and may serve as a potential metastatic driver. Further in vitro and in vivo experiments confirmed that GATA2-mediated transcriptional activation of Notch3 promotes the liver metastasis of Hs766T-L3, and knockdown of either GATA2 or Notch3 reduces the metastatic ability of Hs766T-L3. Therefore, we claim that GATA2 may serve as a metastatic driver of pancreatic cancer and a potential therapeutic target to treat liver metastasis of pancreatic cancer.

• BMB Reports
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• 제46권5호
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• pp.252-257
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• 2013

Fibroblast activation protein (FAP) is a specific serine protease expressed in tumor stroma proven to be a stimulatory factor in the progression of some cancers. The purpose of this study was to investigate the effects of FAP knockdown on tumor growth and the tumor microenvironment. Mice bearing 4T1 subcutaneous tumors were treated with liposome-shRNA complexes targeting FAP. Tumor volumes and weights were monitored, and FAP, collagen, microvessel density (MVD), and apoptosis were measured. Our studies showed that shRNA targeting of FAP in murine breast cancer reduces FAP expression, inhibits tumor growth, promotes collagen accumulation (38%), and suppresses angiogenesis (71.7%), as well as promoting apoptosis (by threefold). We suggest that FAP plays a role in tumor growth and in altering the tumor microenvironment. Targeting FAP may therefore represent a supplementary therapy for breast cancer.

• 한국수정란이식학회지
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• 제24권1호
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• pp.1-14
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• 2009

Ovarian cancer is a significant cause of cancer-related death in women, but the main biological causes remain open questions. Hormonal factors have been considered to be an important determinant causing ovarian cancer. Recent studies have shown that gonadotropin-releasing hormone (GnRH)-I and its analogs have clinically therapeutic value in the treatment of ovarian cancer. In addition, numerous studies have shown that the potential of GnRH-II in normal reproductive system or reproductive disorder. GnRH-I receptors have been detected in approximately 80% of ovarian cancer biopsy specimens as well as normal ovarian epithelial cells and immortalized ovarian surface epithelium cells. GnRH-II receptors have also been found to be more widely expressed than GnRH-I receptors in mammals, suggesting that GnRH receptors may have additional functions in reproductive system including ovarian cancer. The signal transduction pathway following the binding of GnRH to GnRH receptor has been extensively studied. The activation of protein kinase A/C (PKA/PKC) pathway is involved in the GnRH-I induced anti-proliferative effect in ovarian cancer cells. In addition, GnRH-I induced mitogen-activated protein kinase (MAPK) activation plays a role in anti-proliferative effect and apoptosis in ovarian cancer cells and the activation of transcriptional factors related to cellular responses. However, the role of GnRH-I and II receptors, there are discrepancies between previous reports. In this review, the role of GnRH in ovarian cancer and the mechanisms to induce anti-proliferation were evaluated.

• Asian Pacific Journal of Cancer Prevention
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• 제14권4호
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• pp.2295-2299
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• 2013

Background: To explore the role of caveolin-1(CAV-1) gene silencing on MAPK activation in lipopolysaccharide (LPS)-challenged human mammary epithelial cells. Methods: We established a MCF-10ACE of CAV-1 gene silencing from human mammary epithelial cell line MCF-10A by RNAi technology. DNA Microarray were used to detect the expression of inflammation-associated genes in MCF10ACE. Western blotting was used to examine the activation of MAPK in lipopolysaccharide(LPS)-challenged MCF-10A and MCF-10ACE. Moreover, immunofluorescence and Western bloting were performed to detect the co-localization of CAV-1 and toll-like receptor 4 (TLR4) in human mammary epithelial cells. Results: MCF-10ACE exhibited significant increases in inflammation-associated gene expression, especially IL-6 (~7-fold) and IL6R (~17-fold). In addition, LPS-induced p38 MAPK and JNK MAPK activation was significantly increased in MCF-10ACE. Furthermore, CAV-1 co-localized with TLR4 and appeared a negative correlation trend. Conclusion: CAV-1 gene silencing promotes MAPK activation via TLR4 signaling in human mammary epithelial cells response to LPS.

• 한국식품영양학회지
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• 제32권5호
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• pp.565-570
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• 2019

Proteasome inhibitors can improve the efficiency of cancer treatments by inhibiting nuclear factor ${\kappa}B$($NF-{\kappa}B$) activation in cancer cells. Lentils are a type of beans of which consumption of such beans is increasing. The purpose of this study was to investigate the effects of lentils extract (LE) on the proteasomal activities, $NF-{\kappa}B$ activation, and cell cycle in HepG2 human liver cancer cells. LE treatments inhibited proteasomal activities at concentrations of 10, 50, and $100{\mu}g/mL$ respectively, and repressed $NF-{\kappa}B$ activation at concentrations of 1, 10, and $100{\mu}g/mL$ respectively, in HepG2 cells. LE treatments at concentrations of 1, 10, and $100{\mu}g/mL$ respectively, increased sub-G1 cell population in HepG2 cells, which may be the result of apoptosis. The results suggest that LE inhibited $NF-{\kappa}B$ activation partially with its proteasome inhibitory activities, and the increase of sub-G1 cell population was induced partially, by inhibition of $NF-{\kappa}B$ activation in HepG2 cells.

• Molecules and Cells
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• 제44권8호
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• pp.569-579
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• 2021

Cyclase-associated protein 2 (CAP2) has been addressed as a candidate biomarker in various cancer types. Previously, we have shown that CAP2 is expressed during multi-step hepatocarcinogenesis; however, its underlying mechanisms in liver cancer cells are not fully elucidated yet. Here, we demonstrated that endoplasmic reticulum (ER) stress induced CAP2 expression, and which promoted migration and invasion of liver cancer cells. We also found that the ER stress-induced CAP2 expression is mediated through activation of protein kinase C epsilon (PKCε) and the promotor binding of activating transcription factor 2 (ATF2). In addition, we further demonstrated that CAP2 expression promoted epithelial-mesenchymal transition (EMT) through activation of Rac1 and ERK. In conclusion, we suggest that ER stress induces CAP2 expression promoting EMT in liver cancer cells. Our results shed light on the novel functions of CAP2 in the metastatic process of liver cancer cells.