Long Noncoding RNA LINC00909 Induces Epithelial-Mesenchymal Transition and Contributes to Osteosarcoma Tumorigenesis and Metastasis

Abstract

Background. Osteosarcoma (OS) is a malignant tumor that is highly metastatic with a high mortality rate. Although mounting evidence suggests that LINC00909 is strongly associated with the malignant progression of various tumors, the exact role of LINC00909 in OS remains unknown. Therefore, the current study was designed to investigate the relationship between LINC00909 and the malignant progression of OS. Methods. LINC00909 expression was measured in OS cell lines and clinical specimens using RT-qPCR assays. The effects of LINC00909 on OS proliferation, invasion, and migration were calculated both in vitro and in vivo. Apart from that, bioinformatics analyses, FISH, RIP, and luciferase reporter assays were carried out to investigate the downstream target of LINC00909. Rescue experiments were also conducted to investigate the potential mechanisms of action of competitive endogenous RNAs (ceRNAs). Results. In this study, we found that LINC00909 was highly expressed in OS cell lines and clinical specimens. In vivo and in vitro experiments demonstrated that LINC00909 induces epithelial-to-mesenchymal transition (EMT) and contributes to OS tumorigenesis and metastasis. FISH, RIP, and luciferase assays indicated that miR-875-5p is a direct target of LINC00909. Moreover, HOXD9 was validated as the downstream target of miR-875-5p in a luciferase reporter assay and western blotting experiments. Rescue experiments revealed that HOXD9 reversed the effect of LV-sh-LINC00909 on OS cells by positively regulating the PI3K/AKT/mTOR signaling pathway. Conclusion. Collectively, LINC00909 induces EMT and contributes to OS tumorigenesis and metastasis through the PI3K/AKT/mTOR pathway by binding to miR-875-5p to upregulate HOXD9 expression. Targeting the LINC00909/miR-875-5p/HOXD9 axis may have potential in treating OS.

LINC01060 knockdown inhibits osteosarcoma cell malignant behaviors in vitro and tumor growth and metastasis in vivo through the PI3K/Akt signaling

“…Consistent with its overexpression in osteosarcoma samples, LINC01060 knockdown in osteosarcoma cells considerably inhibited cell proliferation, enhanced cell apoptosis, and elicited G1-phase arrest of the cell cycle. In addition, EMT enables osteosarcoma cells to invade and metastasize during the malignant progression of osteosarcoma 38 . Regarding EMT, LINC01060 knockdown decreased the protein contents of N-cadherin and Vimentin as mesenchymal cell factors, whereas it increased the content of E-cadherin as an epithelial marker 4 , 39 .…”

Noncanonical functions of telomerase and telomeres in viruses‐associated cancer

“…promotes the migration and invasion of osteosarcoma cells by upregulating the expression of TERT and TERC, which subsequently activates the Wnt/β-catenin signaling pathway. 36 Furthermore, LINC00909 was found to interact with RNA-binding protein HuR to stabilize TERT and TERC mRNA, which contributes to the sustained expression of TERT and TERC in osteosarcoma cells. 27 Besides the canonical processing of TERC, terc-sRNA has been identified that is upregulated in different tumors and can increase telomerase activity.…”

“…One study found that the long noncoding RNA (lncRNA) LINC00909 induces EMT and contributes to osteosarcoma tumorigenesis and metastasis. The study revealed that LINC00909 promotes the migration and invasion of osteosarcoma cells by upregulating the expression of TERT and TERC, which subsequently activates the Wnt/β‐catenin signaling pathway 36 . Furthermore, LINC00909 was found to interact with RNA‐binding protein HuR to stabilize TERT and TERC mRNA, which contributes to the sustained expression of TERT and TERC in osteosarcoma cells 27 …”

“…Specifically, LMP‐1 activates the hTERT promoter, resulting in increased telomerase activity in B lymphocytes 50 . A few amounts of EBV‐infected B cells will gain to the immortalization by showing telomere dysfunction and potentially triggering the alternative lengthening of telomeres (ALT) mechanism, 36 for example, just lymphoblastoid cell lines (LCLs) with strong telomerase activity successfully navigate through cellular crises and will be immortalized 16,54 . Thus, tumor‐associated viruses can contribute to carcinogenesis by transcriptionally activating cellular genes with oncogenic potentials, such as the hTERT gene 55 …”

HOXD9/miR-451a/PSMB8 axis is implicated in the regulation of cell proliferation and metastasis via PI3K/AKT signaling pathway in human anaplastic thyroid carcinoma

“…The PI3K/AKT pathway has been confirmed to play a key role in dedifferentiation and tumor cell growth in ATC [29]. Previous research suggested that HOXD9 could influence the progression of osteosarcoma malignancy via the PI3K/AKT/mTOR pathway [43]. Through the modulation of the PI3K/AKT/mTOR pathway, miR-451a has the potential to operate as a tumor suppressor in patients with gastric cancer [44].…”