Abstract
BackgroundNon-small cell lung cancer (NSCLC) is the number one cancer killer. Tumor-initiating cells (TICs) are responsible for tumor progression and recurrence. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. This study aims to determine if snoRNAs have important function in lung TICs by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/- cells of 28 primary NSCLC tissues to identify new signatures of TICs; 2) determining prognostic significance of the snoRNA signatures by analyzing the expression in 82 NSCLC tissues with different stages and histological types using quantitative PCR; 3) functionally investigating if the snoRNAs contribute to stemness of lung TICs using in vitro and in vivo assays.ResultsTwenty-two snoRNAs were identified whose changes were specific to the TICs. The expression of two snoRNAs (snoRA3 and snoRA42) was inversely associated with survival of NSCLC patients (P = 0.002, p = 0.001, respectively). Functional analysis indicated that snoRA42 was upregulated in CD133+ cells isolated from NSCLC cell lines compared with the CD133- counterparts. snoRA42 knockdown reduced the proliferation and self-renewal of TICs in vitro. However, ectopic expression of snoRA42 in non-TICs enhanced the potentials of cell proliferation and self-renewal. snoRA42 expression was associated with expression of stem cell-core transcription factors in lung TICs. Blocking snoRA42 expression in TIC xenografts decreased tumorigenesis in mice.ConclusionsThe snoRNA signatures of lung TICs provide potential biomarkers for predicting outcome of NSCLC. snoRA42 is one of the important snoRNAs in regulating features of lung TICs, and thus contributes to lung tumorigenesis.
Highlights
Non-small cell lung cancer (NSCLC) is the number one cancer killer
We propose to determine if aberrant snoRNAs have important function in lung tumor-initiating cells (TICs) by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/− cells of primary NSCLC tissues to identify signatures of TICs; 2) determining prognostic significance of the signatures by analyzing the expression in NSCLC tissues; 3) functionally investigating if the snoRNA signatures may contribute to stemness of lung TICs
Downregulation of snoRA42 inhibits proliferation and self-renewal of lung TICs We explored whether snoRA42 downregulation could inhibit cell growth and proliferation of lung TICs by transfecting CD133+ cells isolated from NSCLC cell lines with snoRA42-short interfering RNAs (siRNAs). snoRA42-siRNA produced more than 75% reduction of snoRA42 expression in the CD133+ cells compared with mock-transfected CD133+ cells or CD133+ cells transfected with the scrambled siRNA (Figure 3B)
Summary
Non-small cell lung cancer (NSCLC) is the number one cancer killer. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. Non-small cell lung cancer (NSCLC) is the leading cause of cancer death for men and women worldwide. With availability of more sensitive radiological imaging studies, more NSCLC patients will be diagnosed while the disease is still at early stage [1,2]. The standard of care for NSCLC is surgery, often followed by chemotherapy [1]. Approximately 84% of those diagnosed with lung cancer will die within five years [1]. The current chemotherapies often have toxicity in normal host tissues, whereas tumor cells rapidly develop resistance to anticancer agents. The developments of biomarkers for identifying NSCLC patients at high risk of recurrence after surgery, and
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