Long Noncoding RNA FEZF1-AS1 Promotes Osteosarcoma Progression by Regulating the miR-4443/NUPR1 Axis

Zhang

Journal Cellular Physiology

et al. 2020

We aimed to investigate the role of exosomal miR‐4443 in metastasis of breast cancer (BCa). In vitro wound‐healing assay and transwell invasion assay were used to investigate effect of miR‐4443 on BCa cells. Animal experiments were performed to confirm its effects in vivo. miR‐4443 promotes the metastasis of BCa cells through downregulating tissue inhibitors of metalloproteinase 2 (TIMP2) and upregulating matrix metalloproteinases (MMPs). Highly invasive BCa cells have a higher expression of miR‐4443 in both cells and exosomes. The exosomes derived from highly invasive BCa cells mainly gather in the primary tumor and liver. In vivo, overexpression of miR‐4443 in noninvasive BCa cells induces liver metastasis, accompanied with downregulated TIMP2, and upregulated MMP‐2 in both the primary tumor and liver. When we armed MCF‐10A exosomes with miR‐4443 inhibitors to treat mice bearing high‐miR‐4443 tumors, exosomes accumulated in the primary tumor, and liver following the upregulation of TIMP2 and downregulation of MMP2, and the metastasis was inhibited. Highly invasive BCa cells destroy natural barriers against metastasis by delivering exosomal miR‐4443 to stromal cells of the primary tumor and impairing TIMP2, consequently activating MMP; circulating exosomal miR‐4443 might promote BCa cells lodging in future metastatic sites through the similar mechanisms.

Section: Discussionmentioning

confidence: 99%

Microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promotes liver metastasis of breast cancer

Zhang

Journal Cellular Physiology

et al. 2020

“…Research evidence shows that the ceRNA modulatory network of lncRNA/miRNA/mRNA is signi cant in the progression, reoccurrence, and therapy of OS [25]. FEZF1-AS1 enhances oncogenesis and malignancy in OS [13,14]. Nevertheless, the function and mechanism of FEZF1-AS1 in OS metastasis remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…FEZF1-AS1, as a ceRNA modulates miR-144/CXCR4 promotes, OS cell proliferation, Warburg effect, and inhibits OS cell apoptosis [13]. FEZF1-AS1 facilitates OS progression via modulating the miR-4443/NUPR1 cascade [14].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of lncRNA FEZF1-AS1 Inhibits metastasis of Osteosarcoma Cells by miR-4456/GALNT10

Zhou

Shen

et al. 2020

Preprint

Background: Osteosarcoma (OS) is among the malignant tumors with high mortality and low survival, especially in children and adolescents. Research shows that LncRNA FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) enhances osteosarcoma progression. Nevertheless, the function and mechanism of FEZF1-AS1 in metastasis of OS remains unclear.Methods: We used qRT-PCR to assay for the expression of FEZF1-AS1, miR-4456, and GALNT10 in OS tissue specimens and cell lines. We also investigated the progression of OS through metastasis using the wound healing and Transwell assays. Moreover, we used the dual-luciferase reporter test, RIP assays, and western blot to validate whether FEZF1-AS1 serves as a competing endogenous RNA (ceRNA), modulating the expression of GALNT10 through sponging miR-4456 in OS.Results: FEZF1-AS1 was up modulated in OS tissues. Silencing FEZF1-AS1 repressed OS cell migration and invasion. microRNA-4456 (miR-4456) was involved in FEZF1-AS1-induced migration and invasion. miR-4456 was down modulated in OS tissue specimens and cell lines. Functionally, the up modulation of miR-4456 reversed the facilitative influence of FEZF1-AS1 on OS cell infiltration and migration. Mechanically, FEZF1-AS1 interacted with miR-4456 in a reciprocal suppressed manner. Moreover, miR-4456 targets GALNT10 via the Luciferase assay. Besides, the up modulation of GALNT10 reversed the migration and invasion inhibited by FEZF1-AS1 knockdown. Silencing of FEZF1-AS1 inhibits OS cell infiltration and migration through miR-4456 /GALNT10 sponging.Conclusion: Herein, we demonstrated that FEZF1-AS1 is a prospective bio signature of metastasis in OS patients. Mechanistically, we showed that the FEZF1-AS1/miR-4456/GALNT10 axis is a target for novel therapeutic development for OS.

“…Insulin and/or leptin resistance (e.g., in obesity) may neutralize this tumor-suppressive pathway, increasing the risk of developing cancer [1]. Supporting this notion, the miR-4443 locus is frequently deleted in cancers based on TCGA data; and a tumor suppressor role for miR-4443 was also reported in other cancer types, i.e., osteosarcoma [2], hepatocellular carcinoma [3], ovarian cancer [4], and glioblastoma [5]. On the other hand, miR-4443 was shown to promote the resistance of non-small cell lung cancer cells, as well as metastatic breast cancer cells, to the chemotherapeutic agent epirubicin [6,7]; and its elevated levels in plasma were suggested as a biomarker of glial tumors [8].…”

Section: Introductionmentioning

confidence: 87%

Leptin-Responsive MiR-4443 Is a Small Regulatory RNA Independent of the Canonic MicroRNA Biogenesis Pathway

Meerson

2020

Biomolecules

The human small RNA miR-4443 is functionally involved in several types of cancer and in the biology of the immune system, downstream of insulin and leptin signaling. Next generation sequencing evidence and structural prediction suggest that miR-4443 is not produced via the canonical Drosha–Exportin 5–Dicer pathway of microRNA biogenesis. We tested this hypothesis by using qRT-PCR to measure miR-4443 and other microRNA levels in HCT-116 cells with Drosha, Exportin 5, and Dicer knockouts, as well as in the parental cell line. Neither of the knockouts decreased miR-4443 levels, while the levels of canonical microRNAs (miR-21 and let-7f-5p) were dramatically reduced. Previously published Ago2-RIP-Seq data suggest a limited incorporation of miR-4443 into RISC, in agreement with the functional studies. The miR-4443 locus shows conservation in primates but not in other mammals, while its seed region appears in additional microRNAs. Our results suggest that miR-4443 is a Drosha, Exportin 5, and Dicer-independent, non-canonical small RNA produced by a yet unknown biogenesis pathway.