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Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
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2019 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, no 17, p. 2141-2156Article in journal (Refereed) Published
Abstract [en]

To investigate the significance of expression of HIF-1 alpha, HIF-2 alpha, and SNAIL1 proteins; and TGF-beta signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-alpha and TGF-beta signaling pathway, including the TGF-beta type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1 alpha/2 alpha, TGF-beta signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1 alpha and HIF-2 alpha were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2 alpha associated with poor cancer-specific survival, while HIF-1 alpha and SNAIL1 did not associate with survival. Moreover, HIF-2 alpha positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1 alpha positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2 alpha. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1 alpha and HIF-2 alpha, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1 alpha and HIF-2 alpha, through its kinase activity. Under hypoxic conditions, HIF-alpha proteins correlated with the activated TGF-beta signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-beta signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-alpha contributes to tumor progression.

Place, publisher, year, edition, pages
Taylor & Francis, 2019. Vol. 18, no 17, p. 2141-2156
Keywords [en]
ALK5, clear cell renal cell carcinoma, HIF-α, SNAIL1, transforming growth factor-β
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-162654DOI: 10.1080/15384101.2019.1642069ISI: 000478075700011PubMedID: 31339433OAI: oai:DiVA.org:umu-162654DiVA, id: diva2:1348838
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-11-04Bibliographically approved
In thesis
1. Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
Open this publication in new window or tab >>Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2019. p. 94
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2060
Keywords
TRAF6, HIF-1α, HIF-2α, HIF-3α, ALK5, Wnt3a, Hypoxic signalling, TGF-β, zebrafish, β-Catenin
National Category
Cancer and Oncology Cell and Molecular Biology
Research subject
Pathology; Oncology
Identifiers
urn:nbn:se:umu:diva-164830 (URN)978-91-7855-140-8 (ISBN)
Public defence
2019-11-29, Major groove_J0, NUS, byggnad 6L, Molecular biology, Umeå, 13:00 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietySwedish Research CouncilCancerforskningsfonden i Norrland
Available from: 2019-11-08 Created: 2019-11-04 Last updated: 2019-11-04Bibliographically approved

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Mallikarjuna, PramodTumkur Sitaram, RaviprakashAripaka, KarthikLjungberg, BörjeLandström, Maréne

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