RESUMO
Systemic therapies, the ultimate strategies for patients with advanced hepatocellular carcinoma (HCC), are suffering from serious clinical challenges, such as the occurrence and development of drug resistance. Treatment resistance aggravates tumor progression partly by inducing tumor metastasis. Regorafenib-resistant HCC cells exhibit a highly striking metastatic phenotype, but the detailed mechanisms underlying these aggressive behaviors remain elusive. Here, we conduct transcriptome sequencing analysis to identify COL5A2 as a crucial driver of the metastatic characteristics of regorafenib-resistant HCC cells. COL5A2 is aberrantly highly expressed in resistant cells, and its genetic depletion significantly suppresses proliferation, migration, invasion, vasculogenic mimicry (VM) formation and lung metastasis in vitro and in vivo, concomitant with the downregulation of VE-cadherin, EphA2, Twist1, p-p38 and p-STAT3 expressions. LIFR is confirmed to be an essential downstream molecule of COL5A2, and its expression is observably elevated by COL5A2 depletion. Ectopic overexpression of LIFR drastically attenuates the proliferation, migration, invasion and VM of regorafenib-resistant cells and represses the expressions of VM-related molecules and the activation of p38/STAT3 signaling pathway. Interestingly, rescue experiments show that the inhibition of the above aggressive features of resistant cells by COL5A2 loss is clearly alleviated by silencing of LIFR. Collectively, our results reveal that COL5A2 promotes the ability of regorafenib-resistant HCC cells to acquire a metastatic phenotype by attenuating LIFR expression and suggest that therapeutic regimens targeting the COL5A2/LIFR axis may be beneficial for HCC patients with therapeutic resistance.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas , Compostos de Fenilureia , Piridinas , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Piridinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Animais , Camundongos , Camundongos Nus , Fenótipo , Metástase Neoplásica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Subunidade alfa de Receptor de Fator Inibidor de LeucemiaRESUMO
The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/ß-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.