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Published: 11 Dec, 2019

Doctoral thesis: Signal pathways crosstalks in progression of kidney cancer

NEWS Canonical and non-canonical TGF-β signaling and hypoxia-inducible factors are associated with renal cell carcinoma, RCC, progression. Investigating these pathways in detail presents us with a potential novel druggable target to stop the progression of RCC. Pramod Mallikarjuna shows this in his doctoral thesis in pathology that he will defend on 18 December

Text: Ola Nilsson

“The observations from these studies will help to further understand these pathways, identify novel biomarkers and druggable targets,” says Pramod Mallikarjuna, PhD-student at the Department of Medical Biosciences.

Renal cell carcinoma, RCC, is the cancer of the kidneys and has a high mortality rate. In his thesis, Pramod Mallikarjuna and the research group he is in, have worked with clinical samples obtained from patients with RCC. They have also used suitable human cell lines to corroborate findings from studies concerning RCC samples. It was observed that TGF-β signaling is associated with clinicopathological prognostic parameters like higher grade, advanced stage, larger tumors, and poor patient survival. It could also seen that non-canonical TGF-β signaling through the liberated intracellular domain of TGF-β receptor I, TβRI, has crucial roles in tumor progression.

VHL is a well-known tumor suppressor gene whose primary targets are the hypoxia-inducible factors. We have shown that VHL has a dampening effect on TGF-β signaling and ubiquitinates TβRI in a Lys48 dependant manner, subjecting it to proteasomal degradation. TGF-β pathway and hypoxia pathway interacts with each other through interactions between HIF-1/2α and TβRI, this crosstalk produces a synergistic effect on RCC progression.  HIF-3α is less studied when compared with HIF-1α or HIF-2α, it exists in several isoforms. HIF-3α was found to be associated with advanced stage and metastasized tumors in clear cell RCC, ccRCC, and associated with larger tumors in papillary renal cell carcinoma, pRCC.

Additionally, it was observed that HIF-3α interacts with tumor necrosis factor receptor-associated factor 6, TRAF6, a crucial component of non-canonical TGF-β signaling.

Pramod Mallikarjuna has a bachelor in engineering from Bengaluru, India, and a master in molecular biology at Umeå University.

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Pramod Mallikarjuna
Postdoctoral fellow
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About the public defence of the doctoral thesis

Pramod Mallikarjuna, Department of Medical Biosciences, Wednesday 18 December at 13.00 o'clock defends his doctoral thesis The role of tranforming growth factor-β signaling and hypoxia inducible factors in renal cell carcinoma. Faculty opponent Anders Bjartell, Lund University. Principal supervisor Maréne Landström.