Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4

Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

“…SALL4 regulates HCC progression by interacting with miRNAs. miR-15a inhibited cell proliferation, migration, and invasion in HCC by downregulating SALL4 [142]. Furthermore, miR-497 directly targeted SALL4 to inhibit SALL4 expression and the self-renewal and metastasis of HCC [91].…”

“…These missense variants maybe increase protein stability, with posttranslational regulation, suggesting the essential genetic involvement of SALL4 in the etiology of POI. However, caution must be taken, since SALL4 is known to function as an oncogene in various death-related tumors [20,134,142,152].…”

Non‐coding RNA‐associated competitive endogenous RNA regulatory networks: Novel diagnostic and therapeutic opportunities for hepatocellular carcinoma

“…Plenty of studies have reported the association of exosomal lncRNAs with HCC. For instance, Ma et al 62 have proposed a mechanism in which exosomes derived from mesenchymal stem cells can transfer miR‐15a to HCC cells to inhibit the cellular proliferation, migration and invasion by negatively regulating SALL4.…”

Elevated Stratifin promotes cisplatin-based chemotherapy failure and poor prognosis in non-small cell lung cancer

“…OS was computed in months from the date of diagnosis to the time of death, regardless of cause, and DFS was defined as the time from surgery to the first event of either disease recurrence or death due to any cause. 21 …”