Abstract
Solamargine (SM) has been shown to have anti‐cancer properties. However, the underlying mechanism involved remains undetermined. We showed that SM inhibited the growth of non‐small cell lung cancer (NSCLC) cells, which was enhanced in cells with silencing of long non‐coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), while it overcame by overexpression of HOTAIR. In addition, SM increased the expression of miR‐214‐3p and inhibited 3‐phosphoinositide‐dependent protein kinase‐1 (PDPK1) gene expression, which was strengthened by miR‐214‐3p mimics. Intriguingly, HOTAIR could directly bind to miR‐214‐3p and sequestered miR‐214‐3p from the target gene PDPK1. Intriguingly, overexpression of PDPK1 overcame the effects of SM on miR‐214‐3p expressions and neutralized the SM‐inhibited cell growth. Similar results were observed in vivo. In summary, our results showed that SM‐inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR‐214‐3p, which ultimately suppressed PDPK1 gene expression. HOTAIR effectively acted as a competing endogenous RNA (ceRNA) to stimulate the expression of target gene PDPK1. These complex interactions and feedback mechanisms contribute to the overall effect of SM. This unveils a novel molecular mechanism underlying the anti‐cancer effect of SM in human lung cancer.
Highlights
Lung cancer is the number one cause of cancer‐related deaths world‐ wide.[1]
Our results demonstrated that HOX transcript antisense RNA (HOTAIR) may be an important target of SM and that inhibition of HOTAIR is involved in the SM‐medi‐ ated inhibition of lung cancer cells
RNA immunoprecipitation (RIP) assay demonstrated a physical interaction between HOTAIR and phosphoinositide‐dependent protein kinase‐1 (PDPK1) protein which was inhibited by SM (Figure 5G). These results suggested that SM exerts its effect on the interaction between HOTAIR and PDPK1 protein by suppressing PDPK1 expression
Summary
Lung cancer is the number one cause of cancer‐related deaths world‐ wide.[1]. Non‐small cell lung cancer (NSCLC), which accounts for 85%. Dysregulation of miRNA is associated with an increasing num‐ ber of human diseases including cancer.[16] Among these, miR‐214‐3p has been reported to be associated with growth, progression and survival in cancers.[17,18,19,20] miR‐214‐3p inhibited proliferation and cell cycle progression by targeting maternal embryonic leucine zipper ki‐ nase (MELK), known as an oncogenic kinase and a key regulator in the malignancy and proliferation of cancer.[21] Induced expression of miR‐214‐3p in oesophageal cancer cells resulted in a decrease in the expressions of survivin and CUG binding protein 1 (CUG‐BP1), an RNA‐binding protein, resulting in enhanced sensitivity of oesophageal cancer cells to cisplatin.[22] The above results highlight the importance of miR‐214‐3p in cancer initiation and progression, suggesting that modulation of miR‐214‐3p may be a key therapeutic target for miRNA‐ based cancer therapies.[23] the role of miRNAs in the biology of lung cancer still remains unclear. We extended these studies and found that SM inhib‐ ited the growth of human lung cancer cells by suppressing PDPK1 expression through a reciprocal interaction between HOTAIR and miR‐214‐3p
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