Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N6-methyladenosine (m6A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m6A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m6A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m6A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m6A modification of ZBTB7A facilitated recognition by the m6A reader YTHDF1/3 complex, enhancing its translation and expression. This m6A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m6A erasure (TRME) system to achieve site-specific demethylation at a single site (m6A_site_411666) within ZBTB7A mRNA, without perturbing m6A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of CRLM.
Xue-Na Chen, Shu-Qiang Zhao, Bochen Liu et al.· Molecular Cancer· 0 citations
Accurate profiling of microRNAs (miRNAs) is often limited by the severe background leakage of conventional enzyme-free DNA amplification. Herein, we develop a 1D DNA nanowire-mediated dispersion-to-localization catalytic hairpin assembly (DL-CHA) platform for the highly sensitive detection of miRNAs. Methodologically, responsive hairpins are physically isolated on spatially dispersed nanowire scaffolds to rigorously suppress target-independent interactions. Upon specific recognition of miR-21, a pseudo-intramolecular cascade is triggered, dynamically cross-linking the scaffolds into a highly fluorescent DNA ladder. As a result, this DL-CHA platform yields an exceptional signal-to-background ratio of 12.4, a broad linear range of 0.05 to 250 nM, and an ultra-sensitive limit of detection of 50 pM without the need for exogenous enzymes. Furthermore, the rigid nanowire architecture ensures robust nuclease resistance and enables highly efficient, transfection-free internalization for the in situ imaging of endogenous miRNAs in living cells. Clinically, the platform accurately discriminated colorectal cancer patients from healthy controls using non-invasive liquid biopsies of human serum. This paradigm offers a robust, low-background molecular tool for precision cancer diagnostics.
Ziheng Tang, Ke-Fan Zheng, Bochen Liu et al.· Biosensors & bioelectronics· 0 citations
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