Long Noncoding RNA H19 Derived from M2 Tumor-Associated Macrophages Promotes Bladder Cell Autophagy via Stabilizing ULK1

Abstract

Purpose. M2-like tumor-associated macrophages (TAMs) are crucial component of immune infiltration in tumor microenvironment (TME), and exosomes derived from TAMs contributed to the regulation of tumor progression through cellular communication. However, in bladder cancer, the role of exosomal components still remains largely unknown. In the current study, we investigated the role of exosomes derived from M2-like TAMs in the regulation of autophagy in bladder cancer (BC) cells. Methods. THP-1 cells were stimulated with IL-4 and IL-13 for the polarization of TAMs, and exosomes were extracted by ultracentrifugation. H19 overexpression plasmid and H19 siRNAs were used in the study. Fluorescent analysis was performed for GFP-LC3 detection. Levels of autophagy and potential target were confirmed by western blot assay and immunoprecipitation. Results. We found that TAMs-exosome treatment significantly enhanced autophagy in BC cells, and the expression of lncRNA H19 was greatly upregulated in TAMs-exosome. Silencing of lncRNA H19 in TAMs-exo obviously decreased the levels of LC3-II expression whereas the p62 levels were increased. Mechanistically, silencing of exosomal H19 from TAMs alleviated ULK1 stabilization in BC cells through promoting K48-linked polyubiquitination of ULK1. At last, we found that overexpression of exosomal H19 from TAMs suppressed the interaction between ULK1 and its specific E3 ligase NEDD4L in BC cells. Conclusion. We revealed the effect of TAMs-exo-contained lncRNA H19 on regulating autophagy of bladder cancer cells, which indicated that targeting TAMs-H19 is a promising therapeutic strategy for the treatment of BC.

Effect of long noncoding RNA NONHSAT070806 on the apoptosis, proliferation, migration, invasion and tumorigenesis of bladder cancer

“…Studies have shown that lncRNAs affect the pathways of division, growth, and cell differentiation, and are also involved in cellular death processes (7,24). Some lncRNAs, including PCGEM1, H19, MALAT1 and HOTAIR, have been well studied, and have been proved as related to prostate, colon, lung, liver, breast, and BC (7,14,25). However, as we know, most of the lncRNAs reported to be involved in the progression of BC have been found to be upregulated in tumor tissues.…”

“…Moreover, recent research has revealed that lncRNAs may have critical regulatory functions in multiple processes of malignancies, including invasion and proliferation, by acting as oncogenes or tumor suppressors (8). Meanwhile, several lncRNAs, including ADAMTS9-AS1, RP11-89, H19, MALAT1 and TUG1, have been revealed to promote BC cell invasion and migration, negatively regulating cell apoptosis and autophagy, facilitating tumorigenesis and ferroptosis, or promoting glutamine-driven anaplerosis of BC cells (11)(12)(13)(14)(15)(16). However, none of them has been used clinically, and the specific lncRNAs involved in BC tumorigenesis have not been fully elucidated.…”

Non-coding RNA and autophagy: Finding novel ways to improve the diagnostic management of bladder cancer

“…Treatment of bladder cancer cells with exosomes isolated from tumor-associated macrophages enhances H19 expression and autophagic response. Inhibition of H19 in TAMs-exosomes blocked autophagy flux ( Guo et al, 2022 ). This study suggests that H19 plays a role in autophagy induction in bladder cancer cells and targeting TAMs-Exosomes-H19 is an encouraging therapeutic approach for the management of bladder cancer.…”

Exosome-encapsulated ncRNAs: Emerging yin and yang of tumor hallmarks

“…For example, exosomal circ-0051443 has been reported to sponge miR-331-3p in order to suppress BAK1 and halt HCC progression ( Chen et al, 2020 ). The circular RNA, namely, hsa_circ_0072309 prevents progression of GC cells by inhibiting PI3K/AKT signaling via activating PPARγ/PTEN signaling ( Guo et al, 2022 ).…”

“…SNHG9 is overexpressed lncRNA in papillary thyroid cancer (PTC) cell-derived exosome, where it enhances cell apoptosis, while, on the other hand, it inhibits cell autophagy of normal thyroid epithelial cell nthy-ori-3 via the YBOX3/P21 pathway ( Wen et al, 2021 ). Tumor-associated macrophages (TAM)-exosomes consist of high levels of lncRNA H19, which significantly enhances autophagy in bladder cancer cells when treated with TAM-exosomes ( Guo et al, 2022 ). In osteosarcoma, exosomal lncRNA OIP5-AS1 could promote autophagy via miR-153 and ATG5 ( Li et al, 2021 ).…”