Elena Kashuba Project

Our research aims to characterize novel pathways of cell fate regulation and to identify new putative diagnostic and/or prognostic markers of cancerogenesis.

Molecular mechanisms of cell transformation

Role of the Mrps18-2 Mitochondrial Protein in Control of Cell Stemness and Cancerogenesis

Our research aims to characterize novel pathways of cell fate regulation and to identify new putative diagnostic and/or prognostic markers of cancerogenesis.

S18 family of mitochondrial ribosomal proteins (MRPS18, S18) consists of three members, S18-1-3. We previously found that ectopic expression of the S18-2 protein led to the immortalization of primary rat fibroblasts, that showed an embryonic stem cell (ESC) phenotype. The S18-1 and -3 have not exhibited such abilities. To understand the differences in protein properties, the evolutionary history of S18 family was analyzed. Based on the phylogenetic analysis and the most parsimonious reconciliation between gene tree and species tree, we concluded on the ancient gene duplication and the following three rounds of the same event in Metazoa, that resulted in the three modern-day S18 proteins in metazoan species. Importantly, the evolutionarily conserved residue Gly132 in S18-2 protein shows genetic polymorphism in colon adenocarcinomas that was confirmed by direct DNA sequencing.

Terminally differentiated rat skin fibroblasts underwent transformation upon ectopic expression of the S18-2 protein. Transformed cells showed increased telomerase activity, cell cycle disturbance and chromosomal instability. We concluded that the S18-2 is an oncoprotein.

In support, we demonstrated that the S18-2 protein is expressed at high levels in endometrial cancers compared to hyperplasia and normal endometrium. Moreover, expression of S18-2 was increased with disease progression in clinical specimens of prostate cancer. The level of induction of epithelial to mesenchymal cell transition (EMT) correlated with the expression level of S18-2 in prostate cancer cell lines. Also, cells acquired increased ability of migration upon S18-2 overexpression, as was evaluated in zebrafish embryo model and in trans-well assay. We found that this is due to increased CXCR4 cell surface expression. The mRNA expression of TWIST2, encoding one of transcription factors that induce EMT upon CXCR4 increase, positively correlated with the S18-2 protein level.

Hence, the S18-2 protein induces EMT through the TWIST2/E-cadherin signaling and, consequently, CXCR4-mediated migration of cancer cells.

Collaborations

  • Ingemar Ernberg, Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology
  • Miriam Mints, Karolinska Institutet, Department of Women's and Children's Health
  • Henrik Zetterberg, Gothenburg University, Institute of Neurobiology and Physiology
  • Beatrice Bercovich, Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel
  • Aaron Ciechanover, Rappaport Family Institute for Research in the Medical Sciences, Technion, Haifa, Israel
  • Lubov Buchynska, NASU, R. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology (IEPOR), Kiev, Ukraine
  • Svetlana Sidorenko, NASU, R. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology (IEPOR), Kiev, Ukraine
  • Larysa Kovalevska, NASU, R. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology (IEPOR), Kiev, Ukraine
  • Boris Snopok, NASU, V. Lashkarev Institute of Semiconductor Physics, Kiev, Ukraine
  • Chanchal Mitra, Hyderabad University, School of Life Sciences, Hyderabad, India 
  • Modra Murovska, Riga Stradins University, A. Kirchenstein Institute of Microbiology and Virology, Riga, Latvia 
  • Irina Holodnuka (Kholodnyuk), Riga Stradins University, A. Kirchenstein Institute of Microbiology and Virology, Riga, Latvia 
  • Maria Issagouliantis, Riga Stradins University, A. Kirchenstein Institute of Microbiology and Virology, Riga, Latvia 
  • Valentina Liakina, Vilnius University, Clinic of Gastroenterology, Nephrourology and Surgery, Vilnius, Lithuania
  • Anatoli Brouchkov, Moscow State University (MSU), Department of Geocryology, Faculty of Geology, Lomonosov, Moscow, Russia

Events

  • The International VACTRAIN/III Swedish-Ukrainian Conference on Cancer Diseases, January 16-17, 2017
  • The European meeting on epstein barr virus and associated malignances, June 2015

Selected Publications

Upregulation of the Chemokine Receptor CCR2B in Epstein‒Barr Virus-Positive Burkitt Lymphoma Cell Lines with the Latency III Program.
Kozireva S, Rudevica Z, Baryshev M, Leonciks A, Kashuba E, Kholodnyuk I
Viruses 2018 05;10(5):

The MRPS18-2 protein levels correlate with prostate tumor progression and it induces CXCR4-dependent migration of cancer cells.
Mushtaq M, Jensen L, Davidsson S, Grygoruk OV, Andrén O, Kashuba V, et al
Sci Rep 2018 02;8(1):2268

The TGF-beta - SMAD pathway is inactivated in cronic lymphocytic leukemia cells.
Matveeva A, Kovalevska L, Kholodnyuk I, Ivanivskaya T, Kashuba E
Exp. Oncol. 2017 Dec;39(4):286-290

Expression Levels of the Uridine-Cytidine Kinase Like-1 Protein As a Novel Prognostic Factor for Hepatitis C Virus-Associated Hepatocellular Carcinomas.
Buivydiene A, Liakina V, Valantinas J, Norkuniene J, Mockiene E, Jokubauskiene S, et al
Acta Naturae ;9(3):108-114

Rat embryonic fibroblasts immortalized by MRPS18-2 protein are target for NK-cells.
Mushtaq M, Pangigadde PN, Darekar S, Dissen E, Kashuba E
Oncotarget 2017 Sep;8(39):64907-64917

Ancient permafrost staphylococci carry antibiotic resistance genes.
Kashuba E, Dmitriev AA, Kamal SM, Melefors O, Griva G, Römling U, et al
Microb. Ecol. Health Dis. 2017 ;28(1):1345574

Expression of the chemokine receptors CCR1 and CCR2B is up-regulated in peripheral blood B cells upon EBV infection and in established lymphoblastoid cell lines.
Kholodnyuk I, Rudevica Z, Leonciks A, Ehlin-Henriksson B, Kashuba E
Virology 2017 12;512():1-7

Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development?
Kashuba E, Mushtaq M
Exp. Oncol. 2017 Mar;39(1):12-16

S18 family of mitochondrial ribosomal proteins: evolutionary history and Gly132 polymorphism in colon carcinoma.
Mushtaq M, Ali RH, Kashuba V, Klein G, Kashuba E
Oncotarget 2016 Aug;7(34):55649-55662

Role of the RB-Interacting Proteins in Stem Cell Biology.
Mushtaq M, Gaza HV, Kashuba EV
Adv. Cancer Res. 2016 ;131():133-57

DNA Tumor Viruses and Cell Metabolism.
Mushtaq M, Darekar S, Kashuba E
Oxid Med Cell Longev 2016 ;2016():6468342

Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1.
Mints M, Mushtaq M, Iurchenko N, Kovalevska L, Stip MC, Budnikova D, et al
Oncotarget 2016 Apr;7(16):22150-8

Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells.
Mushtaq M, Darekar S, Klein G, Kashuba E
PLoS ONE 2015 ;10(8):e0136142

Mitochondrial ribosomal protein S18-2 evokes chromosomal instability and transforms primary rat skin fibroblasts.
Darekar SD, Mushtaq M, Gurrapu S, Kovalevska L, Drummond C, Petruchek M, et al
Oncotarget 2015 Aug;6(25):21016-28

Number of Langerhans cells is decreased in premalignant keratosis and skin cancers.
Shevchuk Z, Filip A, Shevchuk V, Kashuba E
Exp. Oncol. 2014 Mar;36(1):34-7

Contact

Photo archive of group members