Abstract
Background: Hepatocellular carcinoma (HCC) cells exhibit the stemness property, which makes the patient with HCC prone to tumor recurrence and metastasis. Despite the prominent regulatory role of long non-coding RNAs (lncRNAs) in tumor stemness, the roles and molecular mechanisms of LINC00106 in HCC are poorly understood. Methods: LINC00106, let7f and periostin expression levels in tissue specimens and cell lines were assessed through qRT-PCR and immunohistochemistry (IHC). Various in vivo and in vitro assays, namely sphere/colony formation, proportion of side population cells (SP%), invasion, migration, western blot, and murine xenograft model were employed for assessing the stemness and metastatic properties of HCC cells. Luciferase reporter assays, RNA-seq, RNA pull-down, RNA immunoprecipitation (RIP) were conducted to clarificate the target gene and analyze the underlying mechanisms. Results: LINC00106 was prominently upregulated in tissues and cell lines of HCC. Patients having a high LINC00106 level exhibited a poor outcome. Under in vivo and in vitro conditions, the stemness and metastatic properties of HCC cells were augmented by LINC00106. Additionally, LINC00106 was found to sponge let7f to upregulate periostin, which lead to the activation of periostin-associated PI3K-AKT signaling pathway. Moreover, m6A methylation was found to cause LINC00106 upregulation while maintaining LINC00106 RNA transcript stability. Conclusion: m6A methylation triggers the upregulation of LINC00106, which promotes the stemness and metastasis properties in HCC cells by sponging let7f, thereby resulting in periostin activation. The findings indicate the potential of LINC00106 as a diagnostic marker and therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fourth most common and lethal malignancy globally (Kelley and Greten, 2021)
LINC00106 is Upregulated in HCC and is Positively Correlated With Poor Prognosis in Patients With HCC
According to the transwell chamber invasion and migration experiments, the invasion and migration abilities of MHCC-97H and SNU-449 cells clearly decreased after downregulation of LINC00106 (Figures 3A,B), whereas those in Huh7 cells were enhanced after LINC00106 was upregulated (Figure 3C). These results suggested that LINC00106 has an oncogenic role in promoting stemness and metastasis properties in HCC cells
Summary
Hepatocellular carcinoma (HCC) is the fourth most common and lethal malignancy globally (Kelley and Greten, 2021). The CSC population possesses the stemness property, which can make the patients prone to tumor invasion and metastasis (Chen et al, 2021), accounting for the extremely poor prognosis of most patients at the time of HCC diagnosis (Faltas, 2012). Long non-coding (lnc) RNAs represent non-protein-coding RNAs with a length exceeding 200 nucleotides. These RNAs are involved in the acquisition of all carcinoma hallmarks, such as inherent proliferation and survival capabilities through metabolic enhancement and linkage to the carcinoma micro-environment (Statello et al, 2020). Hepatocellular carcinoma (HCC) cells exhibit the stemness property, which makes the patient with HCC prone to tumor recurrence and metastasis. Despite the prominent regulatory role of long non-coding RNAs (lncRNAs) in tumor stemness, the roles and molecular mechanisms of LINC00106 in HCC are poorly understood
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