Disputas- Master of science Kashif Rasheed

disputerer for ph.d.-graden i helsevitenskap og vil offentlig forsvare avhandlingen: “Merkel Cell Polyomavirus and Merkel Cell Carcinoma”

Avhandlingen er tilgjengelig her!
The doctoralthesis!

På grunn av koronautbruddet er auditoriet stengt for publikum.
Disputasen vil i stedet bli strømmet her.
Opptak av disputasen vil være tilgjengelig i en måned.

The auditorium will be closed to the public because of the corona outbreak.
The defense will be streamed here.
A recording of the disputation will be available for one month.


Prøveforelesning over oppgitt emne holdes kl. 10.15, samme sted: 
“Mechanisms of immune evasion by viruses”.
 Prøveforelesningen vil også bli streamet, se her.
 The trail lecture will also be streamed.

Populærvitenskapelig sammendrag av avhandlingen:

Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin cancer.
More than 80% of MCC have Merkel cell polyomavirus (MCPyV) clonally integrated into the human genome (VP-MCC) while the remaining 20% are virus negative (VN-MCC) but linked with mutational genome signature (C[C˃T])N and N[C˃T]C) typical in ultra-violet mutations.
Immunocompromised individuals are at higher risk to develop a MCC compared to immunocompetent individuals.

Inflammation is a central driver for many types of cancer. This thesis aims to identify novel inflammatory mediators and pathways in MCC to contribute to a better understanding of MCC biology, a prerequisite for the development of novel therapeutic approaches.

Several MCPyV variants with polymorphism in their promoter region have been isolated. We have found that MCPyV full-length large T-antigen inhibited viral promoter activities while truncated large T-antigen, which is expressed in MCPyV-positive (VP) MCCs, stimulated viral promoter activities. CCL17/TARC is a chemokine that helps in recruitment of CCR4 receptor expressing cells including regulatory T cells in tumor microenvironment, and supports immunosuppression signals to the tumor microenvironment. IL-33 is a member of IL-1 cytokine and is considered to play both pro- and anti-tumorigenic roles. IL-33 exerts its effect on cells expressing heterodimeric receptors, ST2/IL1RL1 and IL1RAcP.

We have observed a pro-tumorigenic role of IL-33 in MCC and found that MCPyV oncoproteins are linked with elevated expression of CCL17/TARC, IL-33, ST2/IL1RL1 and IL1RAcP in VP-MCC. Immunohistochemical staining on human MCC tissue samples also showed dense staining of these cytokines. Recent findings reported the MCPyV co-infection with high-risk human papilloma virus (HRHPV) -positive cervical cancers.

We demonstrated that MCPyV oncoproteins stimulate the HRHPV16 and HR-HPV18 promoter activity and hence the expression of the cognate HPV16/HPV18 E6 and E7 oncoprotein is elevated. These results indicate that the co-infection of MCPyV may act as a co-factor in the initiation and/or progression of HPV-induced cervical cancer, or in other HPV-associated cancers. Taken together, our studies have highlighted critical role of inflammatory mediators associated with MCC development and targeting inflammatory signaling pathways could be a potential adjuvant therapeutic intervention for MCC.

Hovedveileder Professor Baldur Sveinbjørnsson, Institutt for medisinsk biologi, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet

Professor Ugo Moens, Institutt for medisinsk biologi, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet

Professor Andrew MacDonald, The University of Leeds, England- 1. opponent
Ph.d Alexandre Corthay, Oslo Universityhospital – 2. opponent
Førsteamanuensis Gerd Berge, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet – leder av komité
Disputasleder: Professor Tor Brynjar Stuge, Institutt for medisinsk biologi, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet.

De som ønsker å opponere ex auditorio kan sende e-post til leder av disputasen: Opponents ex auditorio should sign up to the leader of the defense by: tor.brynjar.stuge@uit.no



When: 04.09.20 at 12.15–14.15
Where: Strømmes fra auditorium Cortex
Location / Campus: Tromsø
Target group: Employees, Students, Guests, Invited
Contact: Andrea Jennerwein
E-mail: andrea.jennerwein@uit.no
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