LAMC3 promotes the development of prostate cancer via modulating the cell cycle progression

The senescence-associated secretory phenotype (SASP) plays a critical yet complex role in the progression of prostate cancer (PCa). Although multiple SASP components have been implicated in tumor development, the precise molecular mechanisms through which LAMC3 contributes to PCa pathogenesis remain incompletely understood.

We conducted a comprehensive analysis of SASP components in serum samples from patients with PCa and benign prostatic hyperplasia (BPH) controls. A SASP-related gene signature was established and subsequently validated using nine bulk RNA-seq datasets and two single-cell RNA-seq cohorts. CCK-8, colony formation, EdU assays, etc., were performed to explore the roles of intrinsic LAMC3 on PCa as well as the underlying regulatory pathway.

SASP components were altered between PCa patients and BPH subjects, and the established SASP prognostic model exhibited good performance in patients' prognosis prediction. LAMC3 levels were significantly upregulated in PCa compared to BPH controls. Knockdown of LAMC3 markedly inhibited cellular proliferation, clonogenic potential, and cell cycle progression by inducing G1/S phase arrest. The PI3K/Akt pathway was inhibited after LAMC3 was suppressed, leading to the downregulation of CDKN1A (p21) and CDKN1B (p27) and causing cell cycle arrest. In vivo experiments demonstrated that LAMC3 silencing effectively suppressed tumor growth, and combination therapy with a PI3K inhibitor resulted in synergistic antitumor effects.

The intrinsic LAMC3 promotes prostate cancer progression, and LAMC3 is a key regulator of cell cycle progression in PCa, which was a therapeutic target for PCa management.