Browsing by Subject "proliferation"

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  • Gonda, Yuko; Namba, Takashi; Hanashima, Carina (2020)
    The formation of the neocortex relies on intracellular and extracellular signaling molecules that are involved in the sequential steps of corticogenesis, ranging from the proliferation and differentiation of neural progenitor cells to the migration and dendrite formation of neocortical neurons. Abnormalities in these steps lead to disruption of the cortical structure and circuit, and underly various neurodevelopmental diseases, including dyslexia and autism spectrum disorder (ASD). In this review, we focus on the axon guidance signaling Slit-Robo, and address the multifaceted roles of Slit-Robo signaling in neocortical development. Recent studies have clarified the roles of Slit-Robo signaling not only in axon guidance but also in progenitor cell proliferation and migration, and the maturation of neocortical neurons. We further discuss the etiology of neurodevelopmental diseases, which are caused by defects in Slit-Robo signaling during neocortical formation.
  • Mauramo, Matti; Onali, Tuulia; Wahbi, Wafa; Vasara, Jenni; Lampinen, Anniina; Mauramo, Elina; Kivimäki, Anne; Martens, Stefan; Häggman, Hely; Sutinen, Meeri; Salo, Tuula (2021)
    Previous studies indicate that bilberry with high amounts of phenolic compounds can inhibit carcinogenic processes of colorectal cancer in vitro and in vivo. However, no studies have focused on the effects of bilberry on oral cancer. In this study, we aimed to examine the effects of bilberry powder on oral squamous cell carcinoma (OSCC) cells using both in vitro and in vivo assays. The effects of 0, 1, 10, and 25 mg/mL of whole bilberry powder on the viability, proliferation, migration, and invasion of OSCC (HSC-3) cells were examined and compared with 0.01 mg/mL of cetuximab. Two oral keratinocyte cell lines served as controls. Tumor area was analyzed in zebrafish microinjected with HSC-3 cells and treated with 2.5, 10, or 25 mu g/mL of bilberry powder. Metastases in the head or tail areas were counted. Bilberry powder inhibited the viability, proliferation, migration, and invasion of HSC-3 cells (p < 0.05), which was more pronounced with higher concentrations. Cetuximab had no effect on HSC-3 cell migration or invasion. Compared to controls, the tumor area in zebrafish treated with bilberry powder (10 and 25 mu g/mL) was reduced significantly (p = 0.038 and p = 0.021, respectively), but the number of fish with metastases did not differ between groups. Based on our in vitro and in vivo experiments, we conclude that whole bilberry powder has anti-tumor effects on OSCC cells.
  • Pulkka, Olli-Pekka; Mpindi, John-Patrick; Tynninen, Olli; Nilsson, Bengt; Kallioniemi, Olli; Sihto, Harri; Joensuu, Heikki (2018)
    The molecular mechanisms for the dissemination and metastasis of gastrointestinal stromal tumours (GIST) are incompletely understood. The purpose of the study was to investigate the clinical relevance of integrin alpha 4 (ITGA4) expression in GIST. GIST transcriptomes were first compared with transcriptomes of other types of cancer and histologically normal gastrointestinal tract tissue in the MediSapiens in silico database. ITGA4 was identified as an unusually highly expressed gene in GIST. Therefore, the effects of ITGA4 knock-down and selective integrin alpha 4 beta 1 (VLA-4) inhibitors on tumour cell proliferation and invasion were investigated in three GIST cell lines. In addition, the prognostic role of ITGA4 expression in cancer cells was investigated in a series of 147 GIST patients with immunohistochemistry. Inhibition of ITGA4-related signalling decreased GIST cell invasion in all investigated GIST cell lines. ITGA4 protein was expressed in 62 (42.2%) of the 147 GISTs examined, and expression was significantly associated with distant metastases during the course of the disease and several adverse prognostic features. Patients whose GIST expressed strongly ITGA4 had unfavourable GIST-specific survival and overall survival compared to patients with low or no ITGA4 expression. Taken together, ITGA4 is an important integrin in the molecular pathogenesis of GIST and may influence their clinical behaviour.
  • Vierthaler, Marlene; Rodrigues, Priscila Campioni; Sundquist, Elias; Siponen, Maria; Salo, Tuula; Risteli, Maija (2020)
    Oral tongue squamous cell carcinoma (OTSCC), the most common cancer in the oral cavity, is aggressive and its incidence is increasing globally. Human host defense cationic antimicrobial peptide-18/antimicrobial peptide leucine-leucine-37 (hCAP18/LL-37) plays a complex role in various types of cancers. In the present study, we characterized the effects of exogenous LL-37 on three OTSCC cell lines and determined the expression of hCAP18/LL-37 in oral dysplastic and OTSCC patient samples. Our data revealed that LL-37, especially in high doses, mostly reduced the proliferation of OTSCC cells, but the effect was fluctuating. However, LL-37 stimulated the migration and invasion of OTSCC cells. The high dose of LL-37 also increased the amount of total epidermal growth factor receptor (EGFR) probably due to stabilization of the receptor to the plasma membrane. However, activation of EGFR downstream pathways was mostly decreased. Our immunohistochemical analysis showed that the hCAP18/LL-37 expression was higher in normal/mild dysplasia than in moderate/severe dysplasia and OTSCC. The hCAP18/LL-37 expression did not correlate with clinicopathological features or outcome of OTSCC patients. Our data suggest that LL-37 has a fluctuating effect on proliferation, migration and invasion of OTSCC cells, but it does not seem to play a role in the progression of OTSCC.
  • Arasu, Uma Thanigai; Deen, Ashik Jawahar; Pasonen-Seppänen, Sanna; Heikkinen, Sami; Lalowski, Maciej; Kärnä, Riikka; Härkönen, Kai; Mäkinen, Petri; Lazaro-Ibañez, Elisa; Siljander, Pia R-M; Oikari, Sanna; Levonen, Anna-Liisa; Rilla, Kirsi (2020)
    Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
  • Almahmoudi, Rabeia; Salem, Abdelhakim; Murshid, Sakhr; Dourado, Mauricio Rocha; Apu, Ehsanul Hoque; Salo, Tuula; Al-Samadi, Ahmed (2019)
    We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.
  • Lazaro Ibañez, Elisa; Neuvonen, Katri Maarit; Takatalo-Laine, Sari Maarit; Thanigai Arasu, Uma; Capasso, Cristian; Cerullo, Vincenzo; Rhim, Johng; Rilla, Kirsi; Yliperttula, Marjo Liisa; Siljander, Pia Riitta-Maria (2017)
  • Yliheljo, Emil (Helsingin yliopisto, 2017)
    Denna studie är en del av ett större projekt där man strävar efter att utveckla nya mikroRNA- riktade terapier för hjärtats regeneration. Studien utreder ifall man kan se en ökning i proliferationen av kardiomyocyter efter en induce- rad hjärtinfarkt. Den centrala frågeställningen är ifall neonatalmöss med inducerad hjärtinfarkt under dag 1 uppvisar bättre regenerationsförmåga av hjärtvävnaden än neonatalmöss med indu- cerad infarkt under dag 7. Infarkterna inducerades kirurgiskt genom att ligera LAD-kranskärlet med ett stygn. Till studien användes också referensgrupper med möss utan infarkt, som vid 1 eller 7 dagars ålder genomgått en kirurgisk öppning och slutning av bröstkorgen. Hjärtana avlägsnades 21 dagar efter ingreppen och frystes ner i tissue-TEK gel med hjälp av isopentan, varefter de snittades och markerades med antikroppar mot troponin I och mot Ki-67, ett protein som förekommer i prolifererande celler. Sedan användes fluorecerande sekundäranti- kroppar och färgen DAPI för att markera proverna immunohistokemsikt. Studiens andra mål var att få markeringen att fungera, en förutsättning för att kunna räkna andelen prolifererande kar- diomyocytkärnor. I beräkningen av kardiomyocytkärnor användes ett Matlab-baserat program, Nuquantus. Där- med utreder studien även möjligheterna för automatiserad beräkning av cellkärnor. Programmet lyckades räkna mängden kardiomyocytkärnor men de prolifererande kardiomyocytkärnorna var man tvungen att räkna skiljt för hand. Andelen prolifererande kardiomyocytkärnor jämfördes till slut mellan mössen med infarkter och deras referensgrupper. I studien upptäcktes en signifikant skillnad i den naturliga regenerationsförmågan hos mössen med infarkt under dag 1 och deras referensgrupp. Ingen signifikant skillnad kunde konstateras mellan mössen med infarkt under dag 7 och den andra referensgruppen. Detta indikerar att det neonatala mushjärtat innehar potential för vidare regenerativ forskning, även för det större pro- jektet och stöder tanken att hjärtats naturliga regenerationsförmåga avtar fort efter födseln. (275 ord)
  • Pulkka, Olli-Pekka; Nilsson, Bengt; Sarlomo-Rikala, Maarit; Reichardt, Peter; Eriksson, Mikael; Hall, Kirsten Sundby; Wardelmann, Eva; Vehtari, Aki; Joensuu, Heikki; Sihto, Harri (2017)
    Background: The SLUG transcription factor has been linked with the KIT signalling pathway that is important for gastrointestinal stromal tumour (GIST) tumourigenesis. Its clinical significance in GIST is unknown. Methods: Influence of SLUG expression on cell proliferation and viability were investigated in GIST48 and GIST882 cell lines. The association between tumour SLUG expression in immunohistochemistry and recurrence-free survival (RFS) was studied in two clinical GIST series, one with 187 patients treated with surgery alone, and another one with 313 patients treated with surgery and adjuvant imatinib. Results: SLUG downregulation inhibited cell proliferation, induced cell death in both cell lines, and sensitised GIST882 cells to lower imatinib concentrations. SLUG was expressed in 125 (25.0%) of the 500 clinical GISTs evaluated, and expression was associated with several factors linked with unfavourable prognosis. SLUG expression was associated with unfavourable RFS both when patients were treated with surgery alone (HR = 3.40, 95% CI = 1.67-6.89, P = 0.001) and when treated with surgery plus adjuvant imatinib (HR = 1.83, 95% CI = 1.29-2.60, P = 0.001). Conclusions: GIST patients with high tumour SLUG expression have unfavourable RFS. SLUG may mediate pro-survival signalling in GISTs.
  • Kalervo, Karri (Helsingfors universitet, 2016)
    Sydämen regeneraatiokyky on ihmisellä hyvin rajallinen. Uusia sydänlihassoluja tiedetään muodostuvan jatkuvasti, mutta ei kuitenkaan riittävästi, jotta tuhoutuneen sydänlihaksen korjaantuminen esimerkiksi sydäninfarktin jälkeen olisi tehokasta. Tällä hetkellä ei ole kunnollisia keinoja, joilla voisi korjata jo syntyneitä vaurioita; terapeuttisilla menetelmillä voidaan lähinnä estää uusien vaurioiden syntyä. Hemioksygenaasi-1-entsyymillä (HO-1) tiedetään olevan edullisia vaikutuksia sydämen regeneraatiossa. Tutkimme seeprakalan sydämen kryovauriomallilla HO-1:n merkitystä sydämen regeneraatiossa. Neonataalirotan sydänlihassolujen avulla tutkittiin HO-1:n vaikutusta solujen proliferaatioon. Osoitimme HO-1:n indusoimisen parantavan seeprakalan sydämen funktiota vaurion jälkeen ja lisäävän uusien sydänlihassolujen määrää. Soluviljelymallissa HO-1:n indusointi lisää niin ikään uusien sydänlihassolujen määrää, toisaalta vaikuttaa siltä, että se myös estää proliferaatiota. HO-1 on mielenkiintoinen kohdemolekyyli etsittäessä uusia keinoja sydämen vaurioiden ja niistä seuraavan vajaatoiminnan hoitoon.
  • Ciparyte, Auguste (Helsingin yliopisto, 2020)
    Diabetic ovarian cancer patients who take metformin as part of their anti-diabetic medication generally respond better to DNA-damaging cancer treatment. The molecular mechanisms of the anti-cancer effects of metformin are currently being investigated, but they remain poorly elucidated. Not much is understood about the metformin effect on DNA damage in ovarian cancer cells, where it is of particular importance. When chemotherapy-induced double-stranded DNA breaks are unrepaired, cells reach a point when they cannot tolerate the accumulated DNA damage and die. However, some ovarian cancer cells efficiently employ DNA repair mechanisms, the most prominent being homologous recombination (HR), to overcome DNA damage. Efficient HR causes chemoresistance. An important question is whether metformin has the ability to induce the HR-deficient state in cancer cells, thereby sensitizing them to treatment. This study did not examine HR directly, but it assessed HR indirectly by observing the effect of metformin on recovery from DNA damage in two ovarian cancer cell lines: OVCAR4 (HR-proficient) and Kuramochi (HR-deficient). Additionally, this study evaluated the metformin effect on cell proliferation and apoptosis. OVCAR4 and Kuramochi cells were exposed to varying metformin concentrations (0,5 mM, 5 mM, 10 mM, 15 mM, 20 mM and 25 mM) and for varying durations (24 hours and 48 hours). This study also tested how metformin pretreatment affected the cells’ ability to repair externally (ionizing irradiation) induced DNA damage. The cells were imaged with a high-content imaging system, and percentages of nuclei that were positive for markers for different cellular processes (i.e., DNA damage, proliferation, and apoptosis) were calculated. The study found that only high metformin concentrations, such as 20 mM were able to increase DNA damage and reduce cell proliferation in HR-proficient OVCAR4 cells, both non-irradiated and irradiated. The HR-deficient Kuramochi cell line was generally more sensitive to metformin, particularly with regards to DNA damage, which increased using metformin concentrations < 20 mM. However, 20 mM concentration resulted in the most significant effects. Similarly, only high metformin concentration (25 mM) increased apoptosis, although data were obtained only for a limited number of Kuramochi cells. More experiments on apoptosis would be beneficial. Also, more extensive experiments for the irradiation part are needed to validate these preliminary findings, as well as examining whether high metformin concentrations (> 20 mM) affect specifically the HR-mediated DNA repair pathway.