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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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
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2019 (Engelska)Ingår i: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, nr 17, s. 2141-2156Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Taylor & Francis, 2019. Vol. 18, nr 17, s. 2141-2156
Nyckelord [en]
ALK5, clear cell renal cell carcinoma, HIF-α, SNAIL1, transforming growth factor-β
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-162654DOI: 10.1080/15384101.2019.1642069ISI: 000478075700011PubMedID: 31339433OAI: oai:DiVA.org:umu-162654DiVA, id: diva2:1348838
Tillgänglig från: 2019-09-05 Skapad: 2019-09-05 Senast uppdaterad: 2019-11-23Bibliografiskt 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
2. The role of transforming growth factor‐β signaling and hypoxia‐inducible factors in renal cell carcinoma
Öppna denna publikation i ny flik eller fönster >>The role of transforming growth factor‐β signaling and hypoxia‐inducible factors in renal cell carcinoma
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Renal cell carcinoma (RCC) is the cancer of the kidneys; about 1100 patients with RCC are diagnosed in Sweden each year. RCC can be classified into several subtypes, clear cell renal cell carcinoma (ccRCC) is most common accounting to about 70% of all RCCs, and also the most lethal; papillary renal cell carcinoma (pRCC) accounts to about 10%‐15%, while chromophobe renal cell carcinoma (chRCC) accounts to about 5% of all RCCs. There is a need to study the distinguishing features of RCC subtypes to design treatment. Von Hippel‐Lindau tumor suppressor gene (VHL) is often inactivated in ccRCC, unlike in pRCC or chRCC. Transforming growth factor‐β (TGF‐β) is a cytokine involved in various biological processes such as differentiation, proliferation, apoptosis, migration, andepithelial‐mesenchymal transition. TGF‐β exerts its functions through canonical (Smad‐dependent) and non‐canonical (Smadindependent) signaling pathways. In the first study, we have shown that both canonical and non‐canonical TGF‐β signaling pathways are associated with ccRCC tumor progression. VHL is known to have a dampening effect on TGF‐β signaling in RCC. However, the effects of pVHL status on the TGF‐β signaling pathway in ccRCC and non-ccRCC has not yet been studied in detail. In the second study, we have investigated the effects of the TGF‐β signaling pathway in the presence or absence of pVHL in ccRCC and non‐ccRCC. We show that, in ccRCC, VHL has an inhibiting effect exclusively on canonical TGF‐β signaling, and has no effect on non‐canonical TGF‐β signaling via ALK5‐ICD. In non‐ccRCC, TGF‐β signaling did not have an effect on tumor progression. Further, we demonstrate that VHL, through its ubiquitin ligases activity ubiquitinates ALK5 in a K48 dependent manner and subjects it to proteasomal degradation. During the normoxic conditions, VHL is implicated in ubiquitination and proteasomal degradation of Hypoxia‐inducible factors (HIFs). In hypoxic conditions or when the loss of VHL occurs, HIFs accumulates in the cytoplasm and enters the nucleus to initiate angiogenesis, cell proliferation, and tumor progression. In the third study, we have explored a potential synergistic cross‐talk between TGF‐β signaling and hypoxia in ccRCC. We demonstrate a correlation between TGF‐β signaling components and HIF‐1α/2α in ccRCC. We have also shown that TGF‐β signaling enhances the expression of HIF‐1α/2α and their target genes even under normoxic conditions, dependent on the kinase activity of ALK5 and dictated by the status of VHL. We present novel data that the synergistic crosstalk between hypoxia and TGF‐β is orchestrated through interactions between ALK5 and HIF‐1α/2α. HIF‐3α is only limited studied, compared with HIF‐1α and HIF‐2α. In the fourth study, we have analyzed the roles of HIF‐3α in ccRCC and pRCC and show that HIF‐3α is associated with advanced stage and metastasized tumors. We also found that HIF‐3α is associated with TRAF6, a crucial component of non‐canonical TGF‐β signaling.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2019. s. 84
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2061
Nyckelord
TGF-β, Hypoxia, Renal cell carcinoma, ccRCC, non-ccRCC, transforming growth factor-β, ALK5, pVHL, HIF-α, SNAIL1
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-165401 (URN)9789178551583 (ISBN)
Disputation
2019-12-18, E04, Byggnad 6E, Norrlands universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-11-27 Skapad: 2019-11-23 Senast uppdaterad: 2019-11-25Bibliografiskt granskad

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