RESUMO
The transforming growth factor-ß (TGF-ß) signaling pathway is pivotal in inducing epithelial-mesenchymal transition (EMT) and promoting cancer metastasis. Long non-coding RNAs (lncRNAs) have emerged as significant players in these processes, yet their precise mechanisms remain elusive. Here, we demonstrate that TGF-ß-upregulated lncRNA 1 (TBUR1) is significantly activated by TGF-ß via Smad3/4 signaling in lung adenocarcinoma (LUAD) cells. Functionally, TBUR1 triggers EMT, enhances LUAD cell migration and invasion in vitro, and promotes metastasis in nude mice. Mechanistically, TBUR1 interacts with heterogeneous nuclear ribonucleoprotein C (hnRNPC) to stabilize GRB2 mRNA in an m6A-dependent manner. Clinically, TBUR1 is upregulated in LUAD tissues and correlates with poor prognosis, highlighting its potential as a prognostic biomarker and therapeutic target for LUAD. Taken together, our findings underscore the crucial role of TBUR1 in mediating TGF-ß-induced EMT and metastasis in LUAD, providing insights for future therapeutic interventions.
Assuntos
Adenocarcinoma de Pulmão , Transição Epitelial-Mesenquimal , Proteína Adaptadora GRB2 , Neoplasias Pulmonares , Camundongos Nus , RNA Longo não Codificante , Fator de Crescimento Transformador beta , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína Adaptadora GRB2/metabolismo , Proteína Adaptadora GRB2/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Linhagem Celular Tumoral , Estabilidade de RNA , Transdução de Sinais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células A549 , Masculino , Feminino , Metástase NeoplásicaRESUMO
Liposomal drugs exhibit advantages for cancer therapy, but efficacy is often limited by their rapid clearance from the blood by the reticuloendothelial system, and an inability to target and penetrate tumours. Interestingly, a 21-amino acid SIRP-α- (signal regulatory protein-α) interacting 'self' peptide is reported to inhibit uptake by phagocytes. Also, 'iRGD' a 9-amino acid cyclic peptide that binds αvß3 integrins and neuropilin-1 (NRP-1), promotes targeting and penetration of the drug into tumours. Here we explore the potential of nitrilotriacetic acid-ditetra-decylamine (NTA3-DTDA)-containing liposomes (NTA-liposomes) engrafted with His-tagged forms of 'self' peptide (pCD47) to prolong circulation time in blood after iv administration, and of iRGD peptide (piRGD) to enhance treatment efficacy of doxorubicin-containing liposomes (Caelyx). Our results show that pre-incubation of murine phagocytic DC2.4 and RAW246.7 cells with pCD47 inhibits the uptake of NTA-liposomes in vitro, but engraftment of pCD47 surprisingly reduces liposome lifetime in blood. Engraftment of piRGD promoted binding of NTA-liposomes to murine B16 melanoma and CT26 colorectal carcinoma cells in vitro. Importantly, iv administration of piRGD-engrafted Caelyx was found to significantly inhibit tumour growth and prolong survival in both B16 and CT26 murine tumour models. Our results show that engraftment of piRGD onto Caelyx is a convenient strategy to enhance treatment efficacy.
Assuntos
Lipossomos , Melanoma Experimental , Aminoácidos/uso terapêutico , Animais , Linhagem Celular Tumoral , Doxorrubicina , Lipossomos/química , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Ácido Nitrilotriacético/química , Ácido Nitrilotriacético/uso terapêutico , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
Long noncoding RNAs (lncRNAs) play important roles in the development and progression of human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT1) has been reported to be involved in multiple human cancers, including oesophageal squamous cell carcinoma (ESCC). However, the detailed biological functions, underlying mechanisms and clinical relevance of PCAT1 in ESCC remain unclear. Here, we confirmed that PCAT1 was highly expressed in ESCC tissues and cell lines. Knockdown of PCAT1 inhibited the growth of ESCC cells, whereas overexpression of PCAT1 showed the opposite effect both in vitro and in vivo. Moreover, knockdown of PCAT1 arrested the cell cycle at G2/M phase, reduced the expression of cyclin B1 and CDC2, and caused cells to be more sensitive to paclitaxel. Furthermore, PCAT1 could bind to miR-326, a tumour suppressor in diverse human cancers. Rescue experiments revealed that enforced expression of miR-326 attenuated the promotive effect of PCAT1 on ESCC cell growth. In addition, we discovered that PCAT1 was present in ESCC cell-derived exosomes, was higher in the serum of ESCC patients than those of healthy volunteer donors, and promoted cell growth through exosomes. Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC.
Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Exossomos/metabolismo , Exossomos/ultraestrutura , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , MicroRNAs/genética , RNA Longo não Codificante/genética , Regulação para Cima/genéticaRESUMO
Pancreatic cancer is the fourth leading cause of cancerassociated deaths in Western countries, and ranks sixth among cancerassociated diseases, with the highest mortality rate in China. Deregulation of micro (miR) RNA may contribute to the occurrence and progression of numerous cancers, including pancreatic cancer. In particular, deregulation of microRNA720 (miR720) has been reported in various types of human cancer. However, the expression and biological role of miR720 in pancreatic cancer remains to be elucidated. The present study aimed to investigate the expression and functional role of miR720 in pancreatic cancer and determine the underlying regulatory mechanism. The results demonstrated that miR720 was expressed at low levels in pancreatic cancer tissue samples and cell lines. Upregulating miR720 suppressed pancreatic cancer cell proliferation and invasion in vitro. Additionally, cyclin D1 (CCND1) was identified as the direct target gene of miR720 in pancreatic cancer. Furthermore, CCND1 was significantly upregulated in pancreatic cancer tissues and inversely correlated with miR720 expression. Furthermore, CCND1 reexpression partially abrogated the inhibitory effects of miR720 on pancreatic cancer cells. Overall, miR720 may act as a tumor suppressor by directly targeting CCND1 in pancreatic cancer.