miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4 and CHORDC1

Urabe, Fumihiko; Kosaka, Nobuyoshi; Sawa, Yurika; Yamamoto, Yusuke; Ito, Ken; Kimura, Takahiro; Egawa, Shin; Ochiya, Takahiro

doi:10.1101/646380

Cited by 7 publications

(8 citation statements)

References 33 publications

(11 reference statements)

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“…In recent years, the involvement of extracellular vesicles in tumor progression and metastasis has been extensively studied. However, the mechanism of EV secretion in tumors is still unknown [4,7,37]. Our experiments confirmed that LINC00511 markedly induced the production of MVBs and the release of exosomes in liver cancer and promoted the invasion of HCC.…”

Section: Discussionsupporting

confidence: 66%

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

Peng

Yang

et al. 2021

J Exp Clin Cancer Res

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Background Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Abnormally expressed long noncoding RNAs (lncRNAs) have been confirmed to regulate multiple processes associated with tumor progression. However, the mechanism by which lncRNAs affect exosome secretion remains unclear. Methods The underlying mechanisms of long noncoding RNA LINC00511 (LINC00511) regulation of multivesicular body (MVB) trafficking, exosome secretion, invadopodia formation, and tumor invasion were determined through gene set enrichment analysis (GSEA), immunoblotting, nanoparticle tracking analysis, confocal colocalization analysis, electron microscopy, and invasion experiments. Results We revealed that the tumorigenesis process is associated with a significant increase in vesicle secretion in hepatocellular carcinoma (HCC). Additionally, LINC00511 was significantly more highly expressed in HCC tissues and is related to vesicle trafficking and MVB distribution. We also found that in addition to the formation of invadopodia in HCC progression, abnormal LINC00511 induces invadopodia formation in HCC cells by regulating the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23) to induce the invadopodia formation, which are key secretion sites for MVBs and control exosome secretion. Finally, we revealed that LINC0051-induced invadopodia and exosome secretion were involved in tumor progression. Conclusions Our experiments revealed novel findings on the relationship between LINC00511 dysregulation in HCC and invadopodia production and exosome secretion. This is a novel mechanism by which LINC00511 regulates invadopodia biogenesis and exosome secretion to further promote cancer progression.

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Section: Discussionsupporting

confidence: 66%

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

Peng

Yang

et al. 2021

J Exp Clin Cancer Res

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“…With respect to PCa, potential exosomal biomarkers derived from serum or urine for diagnosis have been widely investigated (Cho et al., 2019; Hao et al., 2015). Interestingly, recent studies showed miRNAs, with potential clinical implications for cancer therapy, are involved in EV secretion from prostate cancer (PCa) cells (Urabe et al., 2020; Urabe et al., 2020). However, only a few functional studies on extracellular vesicles have been conducted to delineate whether PCa exosomes can mechanistically influence bone metastasis.…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from osteogenic tumor activate osteoclast differentiation and concurrently inhibit osteogenesis by transferring COL1A1‐targeting miRNA‐92a‐1‐5p

Sui

Fan

et al. 2021

J of Extracellular Vesicle

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In patients with prostate cancer (PCa), bone lesions appear osteoblastic in radiographs; however, pathological fractures frequently occur in PCa patients, and bone resorption is observed in all metastatic lesions under histopathologic assessment. The mechanisms that balance the activities of osteoblasts and osteoclasts in PCa patients remain unclear. We unexpectedly discovered that PCa exosomes are critical mediators in the regulation of bone homeostasis that results in osteoclastic lesions and thereby promotes tumor growth in bone. We evaluated how exosomes derived from osteoblastic, osteoclastic, and mixed PCa cell lines affect osteoblast and osteoclast differentiation, revealing that all three types of PCa exosomes promoted osteoclastogenesis in vitro and induced osteolysis in vivo. Mechanistically, microRNAs (miRNAs) delivered by PCa exosomes were found to play several key roles in bone homeostasis. Among the delivered miRNAs, miR-92a-1-5p, the most abundant miRNA, downregulated type I collagen expression by directly targeting COLA, and thus promoting osteoclast differentiation and inhibiting osteoblastogenesis. Furthermore, PCa exosomes also markedly reduced type I collagen expression in vivo. Our findings not only offer a novel perspective on tumor bone metastasis, where-contrary to our initial hypothesis-exosomes derived from an osteoblastic tumor induce osteoclast differentiation, but also suggest potential therapeutic targets for PCa bone metastasis. K E Y WO R D S bone homeostasis, bone metastasis, COLA, exosomes, extracellular vesicles, miR-92a-1-5p, prostate cancer  INTRODUCTION Prostate cancer (PCa) is the most common cause of new cancer cases and the second leading cause of cancer-related deaths in males (Siegel et al., 2020). Bone is the most common target organ for high-grade metastatic prostate cancer (Probert et al., 2019). Bone metastasis is detected at autopsy in ∼90% of all PCa patients and remains incurable; the 5-year survival of patients is ∼30%

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“…EVs from the culture medium were isolated by a differential ultracentrifugation (UC) [13,15]. Cells were transplanted into 10 cm plates and changed DMEM with 10% EV-depleted FCS.…”

Section: Ev Isolation and Identificationmentioning

confidence: 99%

“…Recent studies have reported that miRNA could regulate EV secretion to keep itself steady-state level. For instance, miR-26a has been found to be related to EV secretion, resulting in the inhibition of prostate cancer progression [13]. Besides, the relationship between EV secretion and reprogrammed metabolism in cancer cells has not been identified before.…”

Section: Introductionmentioning

confidence: 99%

Let-7a regulates EV secretion and mitochondrial oxidative phosphorylation by targeting SNAP23 in colorectal cancer

Liu

Zhuang

Cai

et al. 2021

J Exp Clin Cancer Res

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Background MicroRNAs (miRNAs) are abundant in tumor-derived extracellular vesicles (EVs) and the functions of extracellular miRNA to recipient cells have been extensively studied with tumorigenesis. However, the role of miRNA in EV secretion from cancer cells remains unknown. Methods qPCR and bioinformatics analysis were applied for determining extracellular let-7a expression from CRC patient serum and cells. Nanosight particle tracking analysis was performed for investigating the effect of let-7a on EV secretion. Luciferase reporter assays was used for identifying targeted genes synaptosome-associated protein 23 (SNAP23). In vitro and in vivo assays were used for exploring the function of let-7a/SNAP23 axis in CRC progression. Bioenergetic assays were performed for investigating the role of let-7a/SNAP23 in cellular metabolic reprogramming. Results let-7a miRNA was elevated in serum EVs from CRC patients and was enriched in CRC cell-derived EVs. We determined that let-7a could suppress EV secretion directly targeting SNAP23. In turn, SNAP23 promotes EV secretion of let-7a to downregulate the intracellular let-7a expression. In addition, we found a novel mechanism of let-7a/SNAP23 axis by regulating mitochondrial oxidative phosphorylation (OXPHOS) through Lin28a/SDHA signaling pathway. Conclusions Let-7a plays an essential role in not only inhibiting EV secretion, but also suppressing OXPHOS through SNAP23, resulting in the suppression of CRC progression, suggesting that let-7a/SNAP23 axis could provide not only effective tumor biomarkers but also novel targets for tumor therapeutic strategies.

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miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4 and CHORDC1

Cited by 7 publications

References 33 publications

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation

Exosomes derived from osteogenic tumor activate osteoclast differentiation and concurrently inhibit osteogenesis by transferring COL1A1‐targeting miRNA‐92a‐1‐5p

Let-7a regulates EV secretion and mitochondrial oxidative phosphorylation by targeting SNAP23 in colorectal cancer

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