umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
Visa övriga samt affilieringar
2019 (Engelska)Ingår i: EBioMedicine, E-ISSN 2352-3964, Vol. 45, s. 192-207Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Ort, förlag, år, upplaga, sidor
Elsevier, 2019. Vol. 45, s. 192-207
Nyckelord [en]
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-161915DOI: 10.1016/j.ebiom.2019.06.046ISI: 000475860000026PubMedID: 31262711Scopus ID: 2-s2.0-85067957867OAI: oai:DiVA.org:umu-161915DiVA, id: diva2:1340885
Tillgänglig från: 2019-08-06 Skapad: 2019-08-06 Senast uppdaterad: 2019-11-04Bibliografiskt granskad
Ingår i avhandling
1. Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
Öppna denna publikation i ny flik eller fönster >>Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Cancer is a disease that involves aggressive changes in the genome and aberrant signals between the living cells. Signalling pathways such as TGF-β (Transforming growth factor-β), Wnt, EGF (epidermal growth factor) and HIF (Hypoxia-inducible factor) evolved to regulate growth and development in mammals. These factors are also implicated for tumorigenesis due to failure or aberrant expression of components in these pathways. Cancer progression is a multistep process, and these steps reflect genetic alterations driving the progressive transformation of healthy human cells into highly malignant derivatives. Many types of cancers are diagnosed in the human population, such as head & neck, cervical, brain, liver, colon, prostate, uterine, breast, and renal cell cancer.

Prostate cancer is the second most common cancer and one of the foremost leading cancer-related deaths in men in the world. Aberrant Wnt3a signals promote cancer progression through the accumulation of β-Catenin. In the first paper, we have elucidated intriguing functions for Tumour necrosis factor receptor-associated factor 6 (TRAF6) as a coregulatory factor for the expression of Wnt-target genes which was confirmed in vivo by using CRISPR/Cas9 genomic editing, in zebrafish. Our data suggest that Wnt3a promotes TRAF6 interaction with Wnt components, and TRAF6 is required for gene expression of β-Catenin as well as for the Wnt-ligand co-receptor LRP5. From the in vivo studies, we elucidated positive regulation of TRAF6, which is crucial for survival and development of zebrafish. This study identifies TRAF6 as an evolutionary conserved co-regulatory protein in the Wnt pathway that also promotes the progression of prostate and colorectal cancer due to its positive effects on Wnt3a signalling.

Hypoxia is a condition due to O2 deprivation, and Hypoxia-inducible factors (HIF) transcription factors are responsible for the maintenance of oxygen homeostasis in living cells. Irregularities in these HIF transcription factors trigger pathological cellular responses for initiation and progression of malignant cancers. Renal cell carcinoma, malignant cancer arising in renal parenchyma and renal pelvis and, hypoxia plays a vital role in its progression. In the second paper, we have investigated the clinicopathological relevance of several hypoxic and TGF-β component proteins such as HIF-1α/2α/3α, TGF-β type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD), SNAI1 and PAI-1 with patient survival in clear cell renal cell carcinoma (ccRCC). We showed that HIF-2α associated with low cancer-specific survival. HIF-2α and SNAI1 positively correlated with ALK5-ICD, pSMAD2/3, PAI-1 and SNAI1 with HIF-2α; HIF-1α positively correlated with pSMAD2/3. Further, under normoxic conditions, our data suggest that ALK5 interacts with HIF-1α and HIF-2α, and promotes their expression and target genes such as GLUT1 and CA9, in a VHL dependent manner through its kinase activity. These findings shed light on the critical aspect of cross-talk between TGF-β signalling and hypoxia pathway, and also the novel finding of an interaction between ALK5 and HIF-α might provide a more in-depth understanding of mechanisms behind tumour progression

In the third paper, an ongoing study, we investigated the role of HIF-3α in the progression of Renal cell carcinoma and its association with the components of TGF-β and HIF pathways. We have observed increased levels of HIF-3α in ccRCC and pRCC (papillary renal cell carcinoma) which are associated with advanced tumour stage, metastasis and larger tumours. Also, we found HIF-3α show a significant positive association with pro-invasive gene SNAI1, which is a crucial regulator of epithelial to mesenchymal transition. TRAF6 an E3 ligase known to be a prognostic marker in RCC and we observed HIF-3α associates with TRAF6.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2019. s. 94
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2060
Nyckelord
TRAF6, HIF-1α, HIF-2α, HIF-3α, ALK5, Wnt3a, Hypoxic signalling, TGF-β, zebrafish, β-Catenin
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Forskningsämne
patologi; onkologi
Identifikatorer
urn:nbn:se:umu:diva-164830 (URN)978-91-7855-140-8 (ISBN)
Disputation
2019-11-29, Major groove_J0, NUS, byggnad 6L, Molecular biology, Umeå, 13:00 (Engelska)
Opponent
Handledare
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseCancerfondenVetenskapsrådetCancerforskningsfonden i Norrland
Tillgänglig från: 2019-11-08 Skapad: 2019-11-04 Senast uppdaterad: 2019-11-04Bibliografiskt granskad

Open Access i DiVA

fulltext(8985 kB)54 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 8985 kBChecksumma SHA-512
43893f98e7729ca9a397fffc43b0be088af3a3c605b2db221b2e42df074217dcad2f5286f6a29a243e5608cb8bccb930fb5078dbc9aa901717f764cfd6b7da42
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltextPubMedScopus

Personposter BETA

Aripaka, KarthikGudey, Shyam KumarZang, GuangxiangSchmidt, AlexejÅhrling, Samaneh ShabaniÖsterman, LennartBergh, Andersvon Hofsten, JonasLandström, Maréne

Sök vidare i DiVA

Av författaren/redaktören
Aripaka, KarthikGudey, Shyam KumarZang, GuangxiangSchmidt, AlexejÅhrling, Samaneh ShabaniÖsterman, LennartBergh, Andersvon Hofsten, JonasLandström, Maréne
Av organisationen
Institutionen för medicinsk biovetenskapPatologiMedicinsk och klinisk genetikUmeå centrum för molekylär medicin (UCMM)Institutionen för integrativ medicinsk biologi (IMB)
I samma tidskrift
EBioMedicine
Cell- och molekylärbiologi

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 54 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 323 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf