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postgraduate thesis: Characterization of stanniocalcin 1 and its implications in hepatocellular carcinoma

TitleCharacterization of stanniocalcin 1 and its implications in hepatocellular carcinoma
Authors
Advisors
Advisor(s):Lo, CLRWong, CM
Issue Date2018
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Chan, K. [陳君璇]. (2018). Characterization of stanniocalcin 1 and its implications in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractDisease burden of hepatocellular carcinoma (HCC) is rising globally. Majority of patients are diagnosed at advanced stage. Moreover, current treatments provide moderate survival benefits implying that ongoing effort is indicated to combat HCC. In this regard, identifying potential biomarkers and druggable targets is a prime strategy to offer benefits for subjects at risk. Hypoxia is a salient feature in HCC. It promotes hepatocarcinogenesis through regulation of hypoxia-responsive genes which govern multiple cellular events including metastasis, chemoresistance, metabolism, and so on. Thus characterization of hypoxia-responsive genetic events would be strategic to discover potential targets in HCC. Stanniocalcin 1 (STC1) overexpression was observed in solid cancers and was shown to exert oncogenic effects. Moreover, it was found to be induced by hypoxia in some cancer cell lines. Yet, being a secreted protein, understanding on the expression and functional roles of secretory STC1 was limited in HCC. In this study, we aimed at examining the expression of STC1 in clinical HCC samples and investigating the functional roles of secretory STC1 in hepatocarcinogenesis. We hereby reported that STC1 was upregulated in clinical HCC tissues when compared to their matched non-tumor tissues. Moreover, serum level of STC1 was elevated in HCC patients when compared to control groups. Importantly, higher serum level of STC1 was correlated with larger tumor size and shorter 5-year disease-free and 5-year overall survival in HCC patients, implying that serum STC1 is a prognostic biomarker. At molecular level, STC1 expression was induced by hypoxia through HIF-1α regulation. Functionally, by means of recombinant human STC1 (rhSTC1) protein, we demonstrated that secretory STC1 enhanced metastatic potential in HCC cells and this could be abrogated by adoption of STC1 antibody in vitro. Effect of STC1 in HCC was further illustrated using knockdown approach. Upon silencing of STC1 in HCC, secretory STC1 level was reduced in vitro and lung metastases were reduced in vivo. Mechanistically, we validated that protein expression of phosphorylated JNK (pJNK) and phosphorylated c-Jun (p-c-Jun) was increased upon treatment of rhSTC1 in HCC cell lines. Effect conferred by rhSTC1 on metastatic potential in HCC cells was abolished upon the co-treatment with JNK inhibitor in vitro. In summary, STC1 expression was upregulated in HCC at both transcript and serum protein levels. Serum STC1 level was correlated with poor prognosis clinically. Using cell line models, hypoxia induced STC1 expression through HIF- 1α regulation and secretory STC1 reinforced metastatic potential through activation of JNK/c-Jun pathway in HCC cells. Our findings elucidated the interaction between hypoxia and secretome elements in the HCC microenvironment. Secretory STC1 is a potential prognostic biomarker and druggable target in HCC.
DegreeDoctor of Philosophy
SubjectGlycoprotein hormones
Liver - Cancer - Pathogenesis
Dept/ProgramPathology
Persistent Identifierhttp://hdl.handle.net/10722/270266

 

DC FieldValueLanguage
dc.contributor.advisorLo, CLR-
dc.contributor.advisorWong, CM-
dc.contributor.authorChan, Kwan-shuen-
dc.contributor.author陳君璇-
dc.date.accessioned2019-05-23T02:26:24Z-
dc.date.available2019-05-23T02:26:24Z-
dc.date.issued2018-
dc.identifier.citationChan, K. [陳君璇]. (2018). Characterization of stanniocalcin 1 and its implications in hepatocellular carcinoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/270266-
dc.description.abstractDisease burden of hepatocellular carcinoma (HCC) is rising globally. Majority of patients are diagnosed at advanced stage. Moreover, current treatments provide moderate survival benefits implying that ongoing effort is indicated to combat HCC. In this regard, identifying potential biomarkers and druggable targets is a prime strategy to offer benefits for subjects at risk. Hypoxia is a salient feature in HCC. It promotes hepatocarcinogenesis through regulation of hypoxia-responsive genes which govern multiple cellular events including metastasis, chemoresistance, metabolism, and so on. Thus characterization of hypoxia-responsive genetic events would be strategic to discover potential targets in HCC. Stanniocalcin 1 (STC1) overexpression was observed in solid cancers and was shown to exert oncogenic effects. Moreover, it was found to be induced by hypoxia in some cancer cell lines. Yet, being a secreted protein, understanding on the expression and functional roles of secretory STC1 was limited in HCC. In this study, we aimed at examining the expression of STC1 in clinical HCC samples and investigating the functional roles of secretory STC1 in hepatocarcinogenesis. We hereby reported that STC1 was upregulated in clinical HCC tissues when compared to their matched non-tumor tissues. Moreover, serum level of STC1 was elevated in HCC patients when compared to control groups. Importantly, higher serum level of STC1 was correlated with larger tumor size and shorter 5-year disease-free and 5-year overall survival in HCC patients, implying that serum STC1 is a prognostic biomarker. At molecular level, STC1 expression was induced by hypoxia through HIF-1α regulation. Functionally, by means of recombinant human STC1 (rhSTC1) protein, we demonstrated that secretory STC1 enhanced metastatic potential in HCC cells and this could be abrogated by adoption of STC1 antibody in vitro. Effect of STC1 in HCC was further illustrated using knockdown approach. Upon silencing of STC1 in HCC, secretory STC1 level was reduced in vitro and lung metastases were reduced in vivo. Mechanistically, we validated that protein expression of phosphorylated JNK (pJNK) and phosphorylated c-Jun (p-c-Jun) was increased upon treatment of rhSTC1 in HCC cell lines. Effect conferred by rhSTC1 on metastatic potential in HCC cells was abolished upon the co-treatment with JNK inhibitor in vitro. In summary, STC1 expression was upregulated in HCC at both transcript and serum protein levels. Serum STC1 level was correlated with poor prognosis clinically. Using cell line models, hypoxia induced STC1 expression through HIF- 1α regulation and secretory STC1 reinforced metastatic potential through activation of JNK/c-Jun pathway in HCC cells. Our findings elucidated the interaction between hypoxia and secretome elements in the HCC microenvironment. Secretory STC1 is a potential prognostic biomarker and druggable target in HCC.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshGlycoprotein hormones-
dc.subject.lcshLiver - Cancer - Pathogenesis-
dc.titleCharacterization of stanniocalcin 1 and its implications in hepatocellular carcinoma-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePathology-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2018-
dc.identifier.mmsid991044104198103414-

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