Disputas- Master of science Kashif Rasheed

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.