Page 112 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

Serbian Association for Cancer Research SDIRSACR

P14
Studying the role of Sigma 2 receptor TMEM97 and PGRMC1 in the progression of Pancreatic ductal
adenocarcinoma

Koutsougianni Fani, Dimitriou Maria Christina, Mavrofora Xanthi, Alexopoulou Dimitra, Sakellaridis Nikolaos, Dimas
Konstantinos

Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, Greece

Keywords: pancreatic neoplasm, progesterone receptor membrane component 1, Siramesine, small interfering RNA,
transmembrane protein 97

Background: Pancreatic cancer remains one of the most lethal malignancies. TMEM97 and PGRMC1, components
of the sigma-2 receptor complex, have been linked to cancer progression and therapy. This study explores their
role in primary PDAC cells, focusing on proliferation, migration, and response to the sigma-2 ligand siramesine.
Materials and Methods: Primary PDAC cells (EANM13_att) were used. TMEM97 and PGRMC1 were silenced via siRNA,
with protein knockdown confirmed by Western blot. SRB assays assessed Siramesine’s cytotoxic and antiproliferative
effects. Clonogenic assays examined long-term proliferation. Migration was tested via transwell assays. Flow cytometry
analyzed cell cycle distribution. In vivo tumorigenesis was studied using xenograft models with receptor-silenced cells.
Results: Silencing TMEM97 and PGRMC1 using siRNA effectively reduced their protein expression. Clonogenic
assays revealed that silencing both receptors significantly reduced the ability of cells to form colonies. Furthermore,
PGRMC1-silenced cells exhibited significant spontaneous cell death, and migration assays indicated that PGRMC1
may be essential for the migratory capacity of pancreatic cancer cells. In vivo, the results showed that silencing
TMEM97 reduces the tumorigenic capacity of PDAC cells, resulting in a delayed appearance and growth of
tumors. Conversely, PGRMC1, silencing was not found to significantly affect tumor growth compared to control
(scrambled siRNA) tumors. The cytotoxicity of siramesine was found to be independent of the status of both
TMEM97 and PGRMC1 while flow cytometry demonstrated siramesine-induced G0/G1 arrest across all groups.
Conclusions: Silencing PGRMC1 revealed that this receptor may significantly influence certain properties of pancreatic
cancer cells in vitro, such as survival and, importantly, migration. Conversely, TMEM97 was found to have a significant
impact on PDAC progression in vivo, delaying tumor appearance and growth. The results suggest that both PGRMC1
and TMEM97 are critical for various features of cancer cell positioning, making them potential therapeutic targets
in pancreatic cancer. It is also noteworthy that the results of the current study suggest that Siramesine may act
independently of the presence of the receptors.

Acknowledgments and funding: The research was supported by the Hellenic Foundation for Research and Innovation
(HFRI) (Program Number:15583).

P15

Impact of high-risk HPV E6 oncoproteins on the Notch signalling pathway

Toni Rendulić*, Josipa Skelin Ilić*, Katarina Soža, Vjekoslav Tomaić

Laboratory of Molecular Virology and Bacteriology, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia

Keywords: HPV, oncoproteins, Notch signalling

Background: Human papillomaviruses (HPVs) comprise a diverse family of small DNA viruses that infect epithelial cells.
Among the different HPV genera, alpha (α) and beta (β) types are of particular interest due to their relevance to human
health. α-HPVs mainly infect mucosal tissues, with high-risk types such as HPV16 and HPV18 being key contributors to
cervical cancer. β-HPVs are commonly linked to harmless skin infections, although specific β-types such as HPV5 and
HPV8 have been identified as cofactors in the development of skin cancers. To enable viral survival and proliferation
within host cells, both α- and β-HPVs employ their respective E6 oncoproteins, which subvert cellular processes
through protein-protein interactions. For example, α-E6s utilize their LXXLL binding motif to hijack the E6AP ubiquitin-
ligase in order to target the p53 tumour suppressor for proteasomal degradation. Using the same binding motif,

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