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RISS 인기검색어
- 검색키워드
- 저자 : ( Nicole Pui Yu Ho ) (검색결과 3 건)
- 무료
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UBE2T: A Molecular Regulator for Cancer Stemness in Hepatocellular Carcinoma
( Nicole Pui-yu Ho ),( Terence Kin Wah Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1
Aims: Increasing evidence showed that cancer stem cells (CSCs) play a critical role in regulating the tumor relapse and ther apeutic resistance of hepatocellular carcinoma (HCC). Given high molecular similarities between liver CSCs and normal liver stem cells, we have enriched the normal stem cell populations by establishing a mouse partial hepactectomy model order to identify critical molecules involved in regulation of liver CSCs. By comparing the expression profiles between the early regen erating liver and intact one, UBE2T was found to be highly up regulated. This, together with the data showing upregulation of UBE2T in enriched liver CSC populations, suggest the role of UBE2T on regulating liver CSCs. Methods: We evaluated the clinic-pathological relevance of UBE2T by qPCR, western blot and immunohistochemical analyses. Lentiviral-based overexpression and knockdown ap proaches were performed to characterize the functional roles of UBE2T in regulating liver CSCs. The protein binding partner of UBE2T was identified by mass spectrometry analysis. Results: By qPCR analysis, UBE2T mRNA overexpression is found in over 90% of HCC samples and is associated with aggressive tumor behavior and poorer patients’ survival. Over expression of UBE2T protein level in HCC clinical samples was further confirmed by western blot and IHC analyses. Using lentiviral based knockdown approach, suppression of UBE2T inhibited liver CSC properties, including self-renewal, tumori genicity, drug resistance and expression of liver CSC markers. Using orthotopic liver xenograft model, UBE2T suppression led to decrease in tumor burden as well as lung metastasis in vivo. Mechanistically, we found UBE2T interacts with E3 ligase Mule and regulates its expression via ubiquitation. Since we further found that UBE2T mediates liver CSC function through Mule-mediated β-catenin activation. Conclusions: We have uncovered a novel UBE2T mediated sig naling cascade in regulation of liver CSCs. Developing a specific inhibitor targeting this pathway may be a novel approach for HCC treatment.
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UBE2T: A Molecular Regulator for Cancer Stemness in Hepatocellular Carcinoma
( Nicole Pui-yu Ho ),( Terence Kin Wah Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1
Aims: Increasing evidence showed that cancer stem cells (CSCs) play a critical role in regulating the tumor relapse and ther apeutic resistance of hepatocellular carcinoma (HCC). Given high molecular similarities between liver CSCs and normal liver stem cells, we have enriched the normal stem cell populations by establishing a mouse partial hepactectomy model order to identify critical molecules involved in regulation of liver CSCs. By comparing the expression profiles between the early regen erating liver and intact one, UBE2T was found to be highly up regulated. This, together with the data showing upregulation of UBE2T in enriched liver CSC populations, suggest the role of UBE2T on regulating liver CSCs. Methods: We evaluated the clinic-pathological relevance of UBE2T by qPCR, western blot and immunohistochemical analyses. Lentiviral-based overexpression and knockdown ap proaches were performed to characterize the functional roles of UBE2T in regulating liver CSCs. The protein binding partner of UBE2T was identified by mass spectrometry analysis. Results: By qPCR analysis, UBE2T mRNA overexpression is found in over 90% of HCC samples and is associated with aggressive tumor behavior and poorer patients’ survival. Over expression of UBE2T protein level in HCC clinical samples was further confirmed by western blot and IHC analyses. Using lentiviral based knockdown approach, suppression of UBE2T inhibited liver CSC properties, including self-renewal, tumori genicity, drug resistance and expression of liver CSC markers. Using orthotopic liver xenograft model, UBE2T suppression led to decrease in tumor burden as well as lung metastasis in vivo. Mechanistically, we found UBE2T interacts with E3 ligase Mule and regulates its expression via ubiquitation. Since we further found that UBE2T mediates liver CSC function through Mule-mediated β-catenin activation. Conclusions: We have uncovered a novel UBE2T mediated sig naling cascade in regulation of liver CSCs. Developing a specific inhibitor targeting this pathway may be a novel approach for HCC treatment.
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( Nicole Pui Yu Ho ),( Bowie Lik Ling Cheng ),( Irene Oi Lin Ng ),( Terence Kin Wah Lee ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Frequent relapse and drug resistance may be attributed to the existence of tumor-initiating cells (T-ICs) in hepatocellular carcinoma (HCC). We investigated the functional role and clinical significance of Interleukin-receptor associated kinase 1 (IRAK1) in regulation of liver tumor-initiating cells (T-ICs) and sorafenib resistance, aiming to develop a novel therapeutic strategy against HCC. Methods: We evaluated the clinic-pathological relevance of IRAK1 in HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize functional roles of IRAK1 in regulation of liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations was identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of IRAK1/4 inhibitor and sorafenib was tested in vivo. Results: From transcriptome sequencing, we identified IRAK1 in TLR/IRAK pathway to be significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at mRNA and protein levels, and correlated with larger tumor size. Interestingly, IRAK4, an upstream regulator of IRAK1, was also found to be consistently upregulated. Through lentiviral based knockdown and overexpression approaches, we demonstrated that IRAK1 regulates traits of liver T-ICs. Similar phenotypic effects were observed when HCC cells were treated with IRAK1/4 inhibitor. Through RNA sequencing analysis by comparing expression profiles between sh-IRAK1 and control cells, we identified Aldo-Keto Reductase Family 1, Member 10 (AKR1B10) as a downstream target of IRAK1. AKR1B10 was found to be overexpressed in HCC, and correlated with IRAK1 expression. Functional analysis demonstrated that knockdown of AKR1B10 offset the IRAK1 induced T-IC functions through regulating AP-1 complex. Using HCC xenograft model, we found that IRAK1/4 inhibitor in combination with sorafenib demonstrated a maximal tumor suppressive effect. Conclusions: IRAK1/AP-1/AKR1B10 signaling cascade regulates liver T-ICs and sorafenib sensitivity. Targeting IRAK1 alone or in combination with sorafenib might be a novel strategy against HCC.
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