Tumor‐derived exosomal miR‐19b‐3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway

Abstract

Numerous reports have elucidated the important participation of exosomes in the communication between tumor cells and other cancer‐related cells including tumor‐associated macrophages (TAMs) in microenvironment. However, the interchange of exosomes between tumor cells and TAMs in the progression of lung adenocarcinoma (LUAD) remains largely enigmatic. Herein, we discovered that LUAD cells induced the M2 polarization of TAMs and the M2‐polarized macrophages facilitated LUAD cell invasion and migration and tumor metastasis in vivo. In detail, LUAD cells secreted exosomes to transport miR‐19b‐3p into TAMs so that miR‐19b‐3p targeted PTPRD and inhibited the PTPRD‐mediated dephosphorylation of STAT3 in TAMs, leading to STAT3 activation and M2 polarization. Also, the activated STAT3 transcriptionally induced LINC00273 in M2 macrophages and exosomal LINC00273 was transferred into LUAD cells. In LUAD cells, LINC00273 recruited NEDD4 to facilitate LATS2 ubiquitination and degradation, so that the Hippo pathway was inactivated and YAP induced the transcription of RBMX. RBMX bound to miR‐19b‐3p to facilitate the packaging of miR‐19b‐3p into LUAD cell‐derived exosomes. Collectively, our results revealed the mechanism underlying the interactive communication between LUAD cells and TAMs through elucidating the exchange of exosomal miR‐19b‐3p and LINC00273 and proved the prometastatic effect of the interchange between two cells. These discoveries opened a new vision for developing LUAD treatment.

M2-Macrophage-Derived Exosomes Promote Meningioma Progression through TGF-β Signaling Pathway

“…In recent years, exosomes have attracted much attention as mediators of intercellular communication in the TME [ 21 , 22 ]. Mounting basic studies have reported that stromal-cell-derived exosomes play a critical role in regulating tumorigenesis and TME remodeling by transferring diverse contents such as miRNA, DNA, and cytokines [ 23 – 25 ]. Importantly, exosomes have been shown to be an important means through which macrophages interact with tumor cells.…”

The interplay between noncoding RNA and YAP/TAZ signaling in cancers: molecular functions and mechanisms

“…In turn, activated YAP induced the transcription of RNA-binding motif protein encoded on the X chromosome (RBMX). By binding to miR-19b-3p, RBMX facilitated the packaging of miR-19b-3p into LUAD cell-derived exosomes [ 99 ]. Collectively, the miR-19b-3p/LINC00273/YAP feedback loop contributed to the communication between lung cancer cells and tumor-associated macrophages.…”

Exosomes as Crucial Players in Pathogenesis of Systemic Lupus Erythematosus

“…Furthermore, mature DC exosomes can promote osteogenic differentiation and improve bone regeneration by transporting miRNA-335 (miR-335) in thighbone-deficient thymic rats [ 46 ]. Moreover, tumor-derived exosomes can promote the polarization of M2 macrophages, while exosomes carrying miRNA-19b-3p (miR-19b-3p) can promote lung cancer metastasis via the Hippo pathway [ 47 ]. Finally, exosomes from hepatocellular carcinoma (HCC) cells can promote tumorigenesis by secreting sonic hedgehog (Shh) protein [ 48 ], which is closely related to both embryonic development and histogenesis in mammals.…”