Tumor-derived exosomal HOTAIRM1 regulates SPON2 in CAFs to promote progression of lung adenocarcinoma

Abstract

Objective SPON2 is one of the extracellular matrix proteins, which is closely related to the progression of a variety of tumors including non-small cell lung cancer (NSCLC), but its upstream regulation mechanism remains unclear. Our research aims to find the specific regulatory pathway of SPON2 by exploring the potential crosstalk between tumor cells and cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME) of NSCLC. Methods We analyzed T1 lung adenocarcinoma samples from TCGA and screened extracellular matrix proteins that indicate poor prognosis. Expression level of SPON2 was verified by qPCR in clinical samples. The exosomes of NSCLC cell supernatant were extracted and identified by nanoparticle tracking analysis (NTA) and transmission electron microscope, western blots. The exosomes and CAFs were co-cultured, and cell migration and Matrigel invasion assay were used to evaluate the effect of CAFs on the migration and invasion of NSCLC cells. The interaction between LncRNA and miRNA was verified by Targetscan prediction, luciferase reporter assay, and RNA binding protein immunoprecipitation (RIP). Results We found that the expression of SPON2 was up-regulated in clinical T1a stage NSCLC patients. The expression of lnc HOTAIRM1 (HOTAIRM1) in exosomes secreted by NSCLC tissues increased. After exosomal HOTAIRM1 entered CAFs, HOTAIRM1 can adsorb miR-328-5p to up-regulate the expression of SPON2 in CAFs. Up-regulation of SPON2 in CAFs could promote the migration and invasion of NSCLC cells. Conclusion Tumor-derived exosomal HOTAIRM1 can transfer into CAFs and competitively adsorb miR-328-5p, and regulate the SPON2 expression of CAFs cells, ultimately promote the progression of NSCLC. The discovery of this regulatory pathway can provide a new potential therapeutic target for the diagnosis and treatment of NSCLC.

Comprehensive analysis of the oncogenic and immunological role of SPON2 in human tumors

“…Ming Wu et al(2023) found that SPON2 promotes the bone metastasis of lung adenocarcinoma via activation of the NF-κB signaling pathway. [45] According to Chen et al, [46] Tumorderived exosomes HOTAIRM1 can transfer to CAFs, regulate the expression of SPON2 in CAFs cells, and ultimately promote the progression of NSCLC. According to Ni et al, [47] SPON2 silencing inhibited the proliferation of LSCC cells through inhibiting the activation of PI3K/AKT signaling.…”

The biological functions and related signaling pathways of SPON2

“…However, this study only analyzed T1 stage samples from TCGA for LUAD. A comprehensive analysis of changes in SPON2 expression across all stages of lung cancer would provide a more robust diagnostic foundation for the diagnosis and treatment of this disease ( 40 ).…”

Long Non-Coding RNAs as Emerging Targets in Lung Cancer

“…A specific example is exosomal HOTAIRM1, which has been observed to modulate the expression of SPON2, an extracellular matrix protein, in cancer-associated fibroblasts. This modulation promotes cancer cell migration and invasion [ 98 ]. Additionally, PCAT6 derived from NSCLC exosomes influences macrophages polarization, promoting the shift towards M2 phenotypes that support tumor growth [ 99 ].…”