Abstract
Lung cancer remains the leading cause of cancer-associated death worldwide. MiR-21 and miR-155 are the most amplified miRNAs in non-small cell lung carcinoma (NSCLC), and are critical promoters of NSCLC progression. However, it remains unclear how miR-21 and miR-155 induce cancer progression, and whether these miRNAs share common targets, such as tumor suppressor genes required to prevent NSCLC. Here we report that miR-21 and miR-155 levels are elevated in NSCLC and are proportional to the progression of the disease. In addition, miR-21 and miR-155 share nearly 30% of their predicted target genes, including SOCS1, SOCS6, and PTEN, three tumor suppressor genes often silenced in NSCLC. Consequently, antagonizing miR-21, miR-155 or both potently inhibited tumor progression in xenografted animal models of NSCLC. Treatment with miR-21 and miR-155 inhibitors in combination was always more effective against NSCLC than treatment with a single inhibitor. Furthermore, levels of miR-21 and miR-155 expression correlated inversely with overall and disease-free survival of NSCLC patients. Our findings reveal that miR-21 and miR-155 promote the development of NSCLC, in part by downregulating SOCS1, SOCS6, and PTEN. Combined inhibition of miR-21 and miR-155 could improve the treatment of NSCLC.
Highlights
Lung cancer is the most common cause of cancerrelated death worldwide [1]
Mimics containing four point mutations in the seed sequences of miR-21 or miR-155 did not change the luciferase activities of the Suppressor of cytokine signaling 1 (SOCS1), Suppressor of cytokine signaling 6 (SOCS6), and phosphatase and tensin homolog (PTEN) 3ʹ-untranslated regions (3ʹ-UTRs) reporters. These results demonstrate that miR-21 and miR-155 downregulate the expression of SOCS1, SOCS6, and PTEN by binding to their 3ʹ-UTRs
We demonstrated that both miR-21 and miR-155 can directly inhibit the expression of SOCS1, SOCS6 and PTEN by binding their 3ʹ-UTRs, uncovering a new layer of the molecular mechanism whereby these genes are repressed in non-small cell lung carcinoma (NSCLC)
Summary
Lung cancer is the most common cause of cancerrelated death worldwide [1]. Non-small cell lung cancer (NSCLC), which encompasses adenocarcinoma, squamous cell carcinoma and large cell carcinoma, accounts for over80% of all lung cancer cases [2]. Suppressor of cytokine signaling 1 (SOCS1) can significantly induce apoptosis and suppress the www.impactjournals.com/oncotarget growth of lung cancer cells [4]. Suppressor of cytokine signaling 6 (SOCS6) is widely expressed in numerous tissues and is down-regulated in many cancers, including lung, colorectal, gastric, ovarian, stomach, thyroid, hepatocellular, and pancreatic cancer [5]. Some studies have demonstrated that phosphatase and tensin homolog (PTEN) functions as a tumor suppressor in NSCLC [7, 8]. These proteins have been implicated in NSCLC, it is not understood how the genes encoding them are regulated during NSCLC progression
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