New insights into the function and mechanisms of piRNA PMLCPIR in promoting PM2.5-induced lung cancer.

Abstract

Introduction: Extensive studies have established the correlation between long-term PM_2.5 exposure and lung cancer, yet the mechanisms underlying this association remain poorly understood. PIWI-interacting RNAs (piRNAs), a novel category of small non-coding RNAs, serve important roles in various diseases. However, their biological function and mechanism in PM_2.5-induced lung cancer have not been thoroughly investigated.

Objectives: We aimed to explore the oncogenic role of piRNA in lung cancer induced by PM_2.5 exposure, as well as the underlying mechanisms.

Methods: We conducted a PM_2.5-induced human lung epithelial cell malignant transformation model. Human samples were used to further verify the finding. In vitro proliferation, migration, and invasion assays were performed to study the function of piRNA. RNA-sequencing was used to elucidate the the mechanisms of how piRNA mediates cell functions. PiRNA pull-down and computational docking analysis were conducted to identify proteins that binding to piRNA. In vivo experiments were used to explore whether inhibition of PMLCPIR could have a therapeutic effect on lung cancer.

Results: We identified a new up-regulated piRNA, termed PM_2.5-induced lung cancer up-regulation piRNA (PMLCPIR), which promotes the proliferation of PM_2.5-transformed cells and lung cancer cells. RNA sequencing revealed ITGB1 as a downstream target of PMLCPIR. Importantly, PMLCPIR binds to nucleolin (NCL) and increases the expression of its target gene, ITGB1, thereby activating PI3K/AKT signaling. The inhibition of PMLCPIR could promote apoptosis in lung cancer cells and enhance their chemosensitivity to anti-tumor drugs.

Conclusion: We systematically identified the alterations of piRNA expression profiles in the PM_2.5-induced malignant transformation model. Then, PMLCPIR was recognized as a novel oncogenic piRNA in PM_2.5-induced lung cancer. Mechanically, PMLCPIR binds to NCL, enhancing ITGB1 expression and activating the ontogenetic PI3K/AKT signaling, potentially contributing to lung cancer progression. This study provides novel insights into the revelation of a new epigenetic regulator in PM_2.5-induced lung cancer.