YKT6 expression, exosome release, and survival in non-small cell lung cancer

Abstract

BackgroundCancer-derived exosomes are involved in metastasis. YKT6 is a SNARE protein that participates in the regulation of exosome production and release, but its role in non-small cell lung cancer (NSCLC) has not been examined.Materials and MethodsUltracentrifugation-purified exosomes from the A549 cell line were studied by CRYO-TEM, nanoparticle tracking analysis and western blot (TSG101 marker). YKT6 was inhibited using a DsiRNA and selected pre-microRNAs. MicroRNAs targeting YKT6 were validated by Renilla/Luciferase assay and western blot. YKT6 expression and its prognostic impact were analyzed in 98 tissue specimens from resected NSCLC patients.ResultsMembranous nanosized vesicles (mode size: 128nm) with TSG101 protein were purified from A549 cells. YKT6 inhibition reduced exosome release by 80.9%. We validated miR-134 and miR-135b as miRNAs targeting YKT6, and transfection with the pre-miRNAs also produced a significant reduction in exosome release. The analysis of YKT6 in tumor samples showed that patients with high levels had shorter disease-free and overall survival.ConclusionsYKT6 is a key molecule in the regulation of exosome release in lung cancer cells and is in turn precisely regulated by miR-134 and miR-135b. Moreover, YKT6 levels impact prognosis of resected NSCLC patients.

miR-134: A Human Cancer Suppressor?

“…Recently, YKT6 was discovered to be a target of miR-134 and dramatically downregulated in lung cancer tissues 88 . High expression of YKT6 might contribute to unsatisfactory prognosis as it promoted emission of exosomes 88 .…”

“…Results suggested high expression of YKT6 with differential inferior disease-free and total survival compared with low expression. In NSCLC patients’ plasma, upregulated YKT6 was accompanied by higher exosomes, which suggested the miR-134-YKT6 pathway might be a larvaceous candidate for lung cancer treatment and prognosis 88 . Dihydropyrimidine dehydrogenase (DPD) tightly correlates with 5-fluorouracil (5-FU), and it has about 80% of the therapeutic effect of 5-FU in cancer treatment 89 .…”

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

“…Cancer cell-derived exosomes are involved in cancer metastasis, 55 and pulmonary malignancies, including NADCs, which are a major cause of morbidity and mortality 56 HIV-associated factors appear to increase the risk of lung cancer and may adversely impact cancer treatment and outcomes in NADC patients. We speculate that cancer cell-derived exosomes, in addition to participating in cancer progression, may facilitate HIV-1 pathogenesis and dissemination to unlikely organ types.…”

The roles and implications of exosomes in sarcoma

“…In addition, exosomes may provide a non-invasive means to assess cancer pathogenesis, progression, and treatment outcomes. Recently, the exosome-shuttling miRNA [73-75], lncRNA [76] and proteins [77] have been demonstrated to be closely related to the prognosis of a variety of tumors, including esophageal cancer, ovarian cancer, lung cancer, bladder cancer, breast cancer and so on [73-78]. These investigations demonstrate the applicability of exosomes as biomarkers of cancer prognosis to sarcoma pateints.…”