Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of CA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of let-7 (lethal-7) family members. Simultaneously with the increase of let-7 miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/let-7 axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.
- MeSH
- antigeny nádorové genetika MeSH
- glykolýza MeSH
- hypoxie buňky MeSH
- karboanhydrasa IX genetika MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- mikro RNA genetika MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- přeprogramování buněk MeSH
- proteiny vázající RNA genetika MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Encapsulation is a well-established method of biomaterial protection, controlled release, and efficient delivery. Here we evaluated encapsulation of monoclonal antibody M75 directed to tumor biomarker carbonic anhydrase IX (CA IX) into alginate microbeads (SA-beads) or microcapsules made of sodium alginate, cellulose sulfate, and poly(methylene-co-guanidine) (PMCG). M75 antibody release was quantified using ELISA and its binding properties were assessed by immunodetection methods. SA-beads showed rapid M75 antibody release in the first hour, followed by steady release during the whole experiment of 7 days. In contrast, the M75 release from PMCG capsules was gradual, reaching the maximum concentration on the 7th day. The release was more efficient at pH 6.8 compared to pH 7.4. The released antibody could recognize CA IX, and target the CA IX-positive cells in 3D spheroids. In conclusion, SA-beads and PMCG microcapsules can be considered as promising antibody reservoirs for targeting of cancer cells.
- MeSH
- antigeny nádorové imunologie metabolismus MeSH
- antitumorózní látky aplikace a dávkování MeSH
- buněčné sféroidy metabolismus MeSH
- karboanhydrasa IX imunologie metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- mikrosféry * MeSH
- monoklonální protilátky aplikace a dávkování imunologie farmakokinetika MeSH
- nádorové biomarkery imunologie metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádory metabolismus patologie MeSH
- PEG-DMA hydrogel * MeSH
- systémy cílené aplikace léků metody MeSH
- uvolňování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In the past decades, highly related members of the protein disulphide isomerase family, anterior gradient protein AGR2 and AGR3, attracted researchers' attention due to their putative involvement in developmental processes and carcinogenesis. While AGR2 has been widely demonstrated as a metastasis-related protein whose elevated expression predicts worse patient outcome, little is known about AGR3's role in tumour biology. Thus, we aim to confront the issue of AGR3 function in physiology and pathology in the following review by comparing this protein with the better-described homologue AGR2. Relying on available data and in silico analyses, we show that AGR proteins are co-expressed or uncoupled in context-dependent manners in diverse carcinomas and healthy tissues. Further, we discuss plausible roles of both proteins in tumour-associated processes such as differentiation, proliferation, migration, invasion and metastasis. This work brings new hints and stimulates further thoughts on hitherto unresolved conundrum of anterior gradient protein function.
- MeSH
- buněčná diferenciace MeSH
- invazivní růst nádoru MeSH
- lidé MeSH
- nádorové proteiny metabolismus MeSH
- nádory metabolismus patologie MeSH
- počítačová simulace MeSH
- pohyb buněk MeSH
- proliferace buněk MeSH
- proteiny metabolismus MeSH
- transportní proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Napriek tomu, že nové biologické a klinické poznatky o nádoroch obličiek neustále pribúdajú, manažment onkologických pacientov aj naďalej zostáva problematický. Významný prelom síce predstavuje zavedenie cielených terapeutík, ktoré majú výrazne lepší terapeutický efekt než konvenčná terapia, ďalší pokrok však možno dosiahnuť iba pomocou identifikácie a validácie relevantných biomarkerov na racionálnu stratifikáciu pacientov a voľbu vhodnej liečebnej stratégie. Cieľom prezentovanej štúdie je objasniť klinický význam anhydrázy IX kyseliny uhličitej (CA IX, z angl. carbonic anhydrase IX), ktorá je úzko viazaná s obličkovými nádormi a má zjavný diagnostický, prognostický, ako aj terapeutický potenciál.
Despite continuously increasing knowledge of biological and clinical features of kidney cancer, management of tumour patients remains problematic. Use of targeted therapeutics - which is much more effective compared to conventional therapy - is an important step forward; however, further progress can be achieved only through identification and validation of relevant biomarkers for rational stratification of patients and selection of proper treatment strategy. The aim of the proposed study is to clarify clinical importance of carbonic anhydrase IX that is tightly associated with kidney tumours and has a conclusive diagnostic, prognostic, as well as therapeutic potential.
