miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction

Abstract

CTC1 is a component of the mammalian CST (CTC1–STN1–TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3′-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.

WITHDRAWN: Experimental verification on “Telomere DNA and ribosomal DNA co-regulation model for cell senescence”

“…There is evidence suggesting a cause-and-effect relationship between the limited cell replicating ability and an individual's lifespan, not only are cells limited in the number of times they can replicate, but each time they divide, they age a little, which defined as Hayflick limit [6]. Cellular aging and limited replication times are known to be associated with telomere shortening, but increasing telomere length still does not prevent the Hayflick limit [7][8][9]. In addition, nematode and fruit fly cells do not divide and telomeres do not shorten.…”

Loneliness, Depression, and Genetics in the Elderly: Prognostic Factors of a Worse Health Condition?

“…The human CTC1-STN1-TEN1 (CST) complex binds to ssDNA and has been implicated in protecting genomic stability under replication stress. Liu et al (2021) [ 107 ] show that the CST complex localizes to replication forks in response to their stalling and protects them from degradation by MRE11 nuclease.…”

Allicin Inhibits Osteosarcoma Growth by Promoting Oxidative Stress and Autophagy via the Inactivation of the lncRNA MALAT1-miR-376a-Wnt/β-Catenin Signaling Pathway

“…MALAT1 was found to be closely related to miR-376a in inhibiting the proliferation of OS. Many studies have found a significant decrease in miR-376a expression in tumor cells, such as rectum adenocarcinoma cell carcinoma [30], laryngocarcinoma [31], and hepatocellular carcinoma [32]. However, studies on miR-376a in OS are relatively scarce.…”