RESUMO
CMTR1, also called IFN-stimulated gene 95 kDa protein (ISG95), is elevated by viral infection in a variety of cells. However, the functions of CMTR1 in colorectal cancer (CRC), especially its roles in tumorigenesis and immune regulation, remain unclear. Here, we first identified CMTR1 as a novel oncogene in colorectal cancer. Based on The Cancer Genome Atlas (TCGA) database exploration and human tissue microarray (TMA) analysis, we found that CMTR1 expression was markedly higher in CRC tissues than in adjacent normal tissues. High CMTR1 expression was correlated with poor prognosis in CRC patients. Knockdown (KD) of CMTR1 significantly suppressed cell proliferation and tumorigenicity both in vitro and in vivo, whereas overexpression of CMTR1 resulted in the opposite effects. KEGG pathway analysis revealed differential enrichment in the JAK/STAT signaling pathway in colorectal cancer cells with CMTR1 KD. Mechanistically, suppression of CMTR1 expression inhibited RNAPII recruitment to the transcription start site (TSS) of STAT3 and suppressed STAT3 expression and activation. Furthermore, the efficacy of PD1 blockade immunotherapy was prominently enhanced in the presence of CMTR1 KD via increased infiltration of CD8 + T cells into the tumor microenvironment. Overall, it appears that CMTR1 plays a key role in regulating tumor cell proliferation and antitumor immunity.
Assuntos
Neoplasias Colorretais , Transdução de Sinais , Humanos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Evasão da Resposta Imune , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Microambiente TumoralRESUMO
PURPOSE: The oncogenic role of circular RNAs (circRNA) has been well studied in cancers including colorectal cancer. However, tumor-suppressive circRNAs and the mechanism through which they exert their antitumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets. EXPERIMENTAL DESIGN: circRNA sequencing, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to find tumor-suppressive and antitumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus (AAV) to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors. RESULTS: circRERE is lowly expressed in colorectal cancer. Overexpression of circRERE inhibits the malignant behaviors of colorectal cancer in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in colorectal cancer as well. Mechanistically, circRERE acts as a competitive endogenous RNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting antitumor immunity. Delivery of circRERE-AAV elicits significant antitumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of colorectal cancer. CONCLUSIONS: These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in antitumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic.