RESUMEN
BACKGROUND: Cancer stem cells (CSCs), responsible for cancer metastasis and recurrence, are generated from non-CSCs after chemo-radiation therapy. This study investigated the induction of CSC potential in non-stem breast cancer cells and the underlying molecular mechanisms in detachment culture. METHODS: Bulk breast cancer cells, or sorted non-CSCs and CSCs were cultured under an attached or detached condition to assess CSC numbers, ability to form tumor spheres, expression of stemness markers, and chemoresistance. Lentivirus carrying CD147 shRNA or cDNA was used to manipulate CD147 expression, while CD147 ligand recombinant cyclophilin A (CyPA) or its inhibitor was used to activate or inhibit CD147 signaling. RESULTS: Detachment promoted anoikis resistance, chemoresistance, sphere formation, self-renewal, and expression of stemness markers in breast cancer cells. Detachment increased functional ALDH+ or CD44highCD24-/low CSCs, and induced CSC potential in ALDH- or CD44 low CD24high non-CSCs. Upon detachment, both CD147 expression and CyPA secretion were enhanced, and CyPA-CD147 activation mediated detachment induced CSC potential in non-CSCs via STAT3 signaling. Clinically, CD147 and pSTAT3 were highly co-expressed and correlated with poor overall survival and tumor recurrence in breast cancer patients. CONCLUSION: This study demonstrates that detachment induces the generation of CSCs from non-stem breast cancer cells via CyPA-CD147 signaling, indicating that targeting CD147 may serve as a potential novel therapeutic strategy for lethal metastatic breast cancer by eliminating induced CSCs.
RESUMEN
Pescadillo (PES1) is a key molecule for ribosome formation in mammalian cells. In this study, human hepatoma C3A cells were reprogrammed by four transcription factors, Oct4, Sox2, Klf4 and c-Myc, into induced cancer stem cells, termed C3A-induced cancer stem cells (C3A-iCSCs). We found that PES1 was up-regulated in C3A-iCSCs and promoted cell proliferation. Moreover, the cancer stem cell marker CD44, which is located in the cytomembrane, translocated to the nucleus and was up-regulated in C3A-iCSCs. Our results suggest that CD44 has a negative effect on miR-105-5p. We found that PES1 is a direct target of, and was negatively regulated by, miR-105-5p. In summary, CD44 regulates PES1 in liver cancer stem cells via miR-105-5p to promote cell growth.
Asunto(s)
Receptores de Hialuranos/metabolismo , Neoplasias Hepáticas/patología , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Proteínas de Unión al ARN/metabolismo , Regiones no Traducidas 3'/genética , Proliferación Celular , Células Hep G2 , Humanos , Factor 4 Similar a Kruppel , Proteínas de Unión al ARN/genética , Regulación hacia ArribaRESUMEN
Local and distant recurrence of malignant tumors following radio- and/or chemotherapy correlates with poor prognosis of patients. Among the reasons for cancer recurrence, preexisting cancer stem cells (CSCs) are considered the most likely cause due to their properties of self-renewal, pluripotency, plasticity and tumorigenicity. It has been demonstrated that preexisting cancer stem cells derive from normal stem cells and differentiated somatic cells that undergo transformation and dedifferentiation respectively under certain conditions. However, recent studies have revealed that cancer stem cells can also be induced from non-stem cancer cells by radiochemotherapy, constituting the subpopulation of induced cancer stem cells (iCSCs). These findings suggest that radiochemotherapy has the side effect of directly transforming non-stem cancer cells into induced cancer stem cells, possibly contributing to tumor recurrence and metastasis. Therefore, drugs targeting cancer stem cells or preventing dedifferentiation of non-stem cancer cells can be combined with radiochemotherapy to improve its antitumor efficacy. The current review is to investigate the mechanisms by which induced cancer stem cells are generated by radiochemotherapy and hence provide new strategies for cancer treatment.