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Article: RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma

TitleRSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma
Authors
KeywordsHepatocellular carcinoma
Next-generation sequencing
Gene mutation
RSK2
Issue Date2021
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
Journal of Hepatology, 2021, v. 74 n. 2, p. 360-371 How to Cite?
AbstractBackground & Aims: Mutational profiling of patient tumors has suggested that hepatocellular carcinoma (HCC) development is mainly driven by loss-of-function mutations in tumor suppressor genes. p90 ribosomal S6 kinase 2 (RSK2) functions as a direct downstream kinase of ERK1/2 and elevated RSK2 expression has been reported to support oncogenic functions in some cancers. We investigated if RSK2 was also dysregulated by inactivating mutations in cancers including HCC. Methods: We performed exome sequencing and targeted DNA sequencing on HBV-associated HCCs to examine recurrent RSK2 mutations. The functional significance and mechanistic consequences of RSK2 mutations were examined in natural RSK2-null HCC cells, and RSK2-knockout HCC cells. The potential downstream pathways underlying RSK2 mutations were investigated by RNA sequencing, qRT-PCR and mass spectrometry. Results: We detected recurrent somatic RSK2 mutations at a rate of 6.3% in our HCC cohorts and revealed that, among many cancer types, HCC was the cancer most commonly harboring RSK2 mutations. The RSK2 mutations were inactivating and associated with a more aggressive tumor phenotype. We found that, functionally, restoring RSK2 expression in natural RSK2-null HBV-positive Hep3B cells suppressed proliferation and migration in vitro and tumorigenicity in vivo. Mechanistically, RSK2-inactivating mutations attenuated a SOS1/2-dependent negative feedback loop, leading to the activation of MAPK signaling. Of note, this RSK2 mutation-mediated MAPK upregulation rendered HCC cells more sensitive to sorafenib, a first-line multi-kinase inhibitor for advanced HCC. Furthermore, such activation of MAPK signaling enhanced cholesterol biosynthesis-related gene expression in HCC cells. Conclusions: Our findings reveal the mechanistic and functional significance of RSK2-inactivating mutations in HCC. These inactivating mutations may serve as an alternative route to activate MAPK signaling and cholesterol metabolism in HCC. Lay summary: In this study, we identified and functionally characterized RSK2-inactivating mutations in human hepatocellular carcinoma and demonstrated their association with aggressive tumor behavior. Mutations in RSK2 drive signaling pathways with known oncogenic potential, leading to enhanced cholesterol biosynthesis and potentially sensitizing tumors to sorafenib treatment.
Persistent Identifierhttp://hdl.handle.net/10722/300223
ISSN
2021 Impact Factor: 30.083
2020 SCImago Journal Rankings: 7.112
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChan, LK-
dc.contributor.authorHo, DWH-
dc.contributor.authorKAM, CS-
dc.contributor.authorChiu, EYT-
dc.contributor.authorLo, ILO-
dc.contributor.authorYau, DTW-
dc.contributor.authorCheung, ETY-
dc.contributor.authorTang, CN-
dc.contributor.authorTang, VWL-
dc.contributor.authorLee, TKW-
dc.contributor.authorWong, CCL-
dc.contributor.authorChok, KSH-
dc.contributor.authorChan, ACY-
dc.contributor.authorCheung, TT-
dc.contributor.authorWong, CM-
dc.contributor.authorNg, IOL-
dc.date.accessioned2021-06-04T08:39:53Z-
dc.date.available2021-06-04T08:39:53Z-
dc.date.issued2021-
dc.identifier.citationJournal of Hepatology, 2021, v. 74 n. 2, p. 360-371-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/300223-
dc.description.abstractBackground & Aims: Mutational profiling of patient tumors has suggested that hepatocellular carcinoma (HCC) development is mainly driven by loss-of-function mutations in tumor suppressor genes. p90 ribosomal S6 kinase 2 (RSK2) functions as a direct downstream kinase of ERK1/2 and elevated RSK2 expression has been reported to support oncogenic functions in some cancers. We investigated if RSK2 was also dysregulated by inactivating mutations in cancers including HCC. Methods: We performed exome sequencing and targeted DNA sequencing on HBV-associated HCCs to examine recurrent RSK2 mutations. The functional significance and mechanistic consequences of RSK2 mutations were examined in natural RSK2-null HCC cells, and RSK2-knockout HCC cells. The potential downstream pathways underlying RSK2 mutations were investigated by RNA sequencing, qRT-PCR and mass spectrometry. Results: We detected recurrent somatic RSK2 mutations at a rate of 6.3% in our HCC cohorts and revealed that, among many cancer types, HCC was the cancer most commonly harboring RSK2 mutations. The RSK2 mutations were inactivating and associated with a more aggressive tumor phenotype. We found that, functionally, restoring RSK2 expression in natural RSK2-null HBV-positive Hep3B cells suppressed proliferation and migration in vitro and tumorigenicity in vivo. Mechanistically, RSK2-inactivating mutations attenuated a SOS1/2-dependent negative feedback loop, leading to the activation of MAPK signaling. Of note, this RSK2 mutation-mediated MAPK upregulation rendered HCC cells more sensitive to sorafenib, a first-line multi-kinase inhibitor for advanced HCC. Furthermore, such activation of MAPK signaling enhanced cholesterol biosynthesis-related gene expression in HCC cells. Conclusions: Our findings reveal the mechanistic and functional significance of RSK2-inactivating mutations in HCC. These inactivating mutations may serve as an alternative route to activate MAPK signaling and cholesterol metabolism in HCC. Lay summary: In this study, we identified and functionally characterized RSK2-inactivating mutations in human hepatocellular carcinoma and demonstrated their association with aggressive tumor behavior. Mutations in RSK2 drive signaling pathways with known oncogenic potential, leading to enhanced cholesterol biosynthesis and potentially sensitizing tumors to sorafenib treatment.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.subjectHepatocellular carcinoma-
dc.subjectNext-generation sequencing-
dc.subjectGene mutation-
dc.subjectRSK2-
dc.titleRSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailChan, LK: lkchan1@HKUCC-COM.hku.hk-
dc.identifier.emailHo, DWH: dwhho@hku.hk-
dc.identifier.emailChiu, EYT: ellechiu@pathology.hku.hk-
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hk-
dc.identifier.emailChok, KSH: chok6275@hku.hk-
dc.identifier.emailChan, ACY: acchan@hku.hk-
dc.identifier.emailCheung, TT: cheung68@hku.hk-
dc.identifier.emailWong, CM: jcmwong@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.authorityChan, LK=rp02289-
dc.identifier.authorityHo, DWH=rp02285-
dc.identifier.authorityWong, CCL=rp01602-
dc.identifier.authorityChok, KSH=rp02110-
dc.identifier.authorityChan, ACY=rp00310-
dc.identifier.authorityCheung, TT=rp02129-
dc.identifier.authorityWong, CM=rp00231-
dc.identifier.authorityNg, IOL=rp00335-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jhep.2020.08.036-
dc.identifier.pmid32918955-
dc.identifier.scopuseid_2-s2.0-85096401703-
dc.identifier.hkuros322676-
dc.identifier.volume74-
dc.identifier.issue2-
dc.identifier.spage360-
dc.identifier.epage371-
dc.identifier.isiWOS:000612194700013-
dc.publisher.placeNetherlands-

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