# Divergent roles of circMPP6 and its parental gene MPP6 in non-small cell lung cancer

## TL;DR

This study shows that circMPP6 and its parental gene MPP6 have opposite effects on non-small cell lung cancer growth, with circMPP6 counteracting tumor promotion.

## Contribution

Reveals divergent roles of circMPP6 and MPP6 in NSCLC, including opposing effects on proliferation and hypoxia signaling.

## Key findings

- circMPP6 and MPP6 regulate distinct gene sets and chromosomal regions in NSCLC.
- circMPP6 reduces lactate and glutathione, while MPP6 increases glutathione and promotes proliferation.
- circMPP6 downregulates SLC7A11, whereas MPP6 upregulates it, with both linked to hypoxia signaling.

## Abstract

Circular RNAs (circRNAs) regulate cancer biology, but their relationships with parental genes remain unclear. We characterized circMPP6, derived from MPP6, and its interplay with MPP6 in non-small cell lung cancer (NSCLC).

circMPP6 was validated by RNase R resistance and Sanger sequencing in A549 cells. Expression of circMPP6 and MPP6 was measured in 10 paired NSCLC tumors and adjacent-tissues. RNA-seq after gain-of-function of circMPP6, MPP6, and SLC7A11 was followed by enrichment analyses and chromosome-level DEG mapping. Proliferation was assessed by CCK-8 and xenografts. Lactate and glutathione were quantified, SLC7A11 protein measured by Western blot, and prognosis analyzed in GEO/TCGA.

MPP6 trended upward in tumors, while circMPP6 was unchanged. circMPP6 and MPP6 were positively correlated in adjacent-tissues but not in tumors. Overexpression of circMPP6 and MPP6 yielded 765 and 334 DEGs, respectively, with shared enrichment of hypoxia-related pathways. 67 genes were upregulated by circMPP6 but downregulated by MPP6, also linked to hypoxia signaling. circMPP6-regulated DEGs were enriched on chromosome 19, whereas MPP6-regulated DEGs clustered on chromosome 17. Functionally, circMPP6 did not alter proliferation, MPP6 enhanced it, and co-expression attenuated MPP6-driven growth in vitro and in vivo. circMPP6 reduced intracellular lactate and glutathione; MPP6 minimally affected lactate and increased glutathione. Consistently, circMPP6 downregulated SLC7A11, whereas MPP6 upregulated it. High-risk circMPP6-driven signatures and high MPP6 expression associated with poorer prognosis.

circMPP6 and MPP6 exert distinct, partially opposing effects on NSCLC growth. In the context of MPP6 overexpression, circMPP6 counteracts tumor-promoting programs, highlighting functional divergence between circRNAs and their parental genes.