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Tanshinones suppress non-small cell lung cancer through up-regulating miR-137.

Great progress has been made in the treatment of lung cancer, notably a diversification in therapeutic drugs including immunotherapies such as those based on PD-1. Among these, there are many anti-disease molecules extracted from Chinese traditional medicine, such as artemisinin and tanshinones. Tanshinones, including Tanshinone I (T1), Tanshinone IIA (T2A), and cryptotanshinone (CT), are the liposoluble constituents of Salia miltiorrhiza, a traditional herb, which has favorable medicinal value. Of particular interest is the cytotoxic effect that tanshinone has on tumor cells, which is thought to occur primarily through the induction of apoptosis and interdiction of cell cycle progression, angiogenesis, cell invasion, and metastasis. Previous studies have indicated that the apoptosis-inducing effect of tanshinones might effectively target and inhibit the growth of human lung cancer cells [1]. Thus, it is reasonable to speculate that tanshinones may play an important role in the treatment of non–small cell lung cancer (NSCLC). Studies have already shown that tanshinone molecules can inhibit the growth of lung cancer cells in vitro [2], and that the mechanism may be through the interruption of cell cycle progression and induction of cell apoptosis, resulting in the up-regulation of miR137 expression. MicroRNAs (miRNAs) are a class of single-stranded small noncoding RNAs, which range from 18–23 nucleotides in length, are encoded by an endogenous gene, and regulate gene expression at the post-transcriptional level. In the tumorigenesis process, miRNAs play a regulatory role and can govern the expressions of tumorassociated genes [3]. We proposed that tanshinones might inhibit NSCLC via regulating the expression of related miRNAs and tested this hypothesis by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Our results showed that tanshinones could up-regulate the expression of miR-137, as evidenced by higher expression of miR-137 in H1299 cells incubated with 4 μM T1, 4 μM T2A, or 5 μM CT (Hao-Xuan Bio-Tech Co., Ltd, Xi’an, China) for 48 h when compared with those in the control cells incubated with 5 μM dimethyl sulfoxide only (Supplementary Fig. S1A). Results from qRT-PCR assays also showed that the expression levels of the miRNAs tested, including let-7b/c, miR-25, miR-32, miR-34a, miR-92a/b, miR-363, and miR-367, were all significantly up-regulated by tanshinones (T1, T2A, and CT). We further found that miR-137 was significantly down-regulated in H1650 (P < 0.01), A549, 95-D, SPCA-1, H358, HCC-827, PC-9, and H23 cells (P < 0.001) when compared with that in the BEAS-2B control cells (Supplementary Fig. S1B). We also found that the effect of tanshinones on NSCLC was inhibited when cells were transfected with miR-137 inhibitor (RiboBio, Guangzhou, China) (Supplementary Fig. S1C,D). These results suggested an association between NSCLC carcinogenesis and the reduction in miR-137 expression. Based on the above findings, we chose the A549 and SPCA-1 cells to investigate the effect of miR-137 on NSCLC cell proliferation. A549 and SPCA-1 cells were transfected with an miR-137 mimic, and the transfection efficiency was evaluated by qRT-PCR, showing that the miR-137 levels did in fact increase in both cell lines (Fig. 1A). Our data revealed that transfection with miR-137 mimic resulted in an inhibition of cell proliferation in both A549 and SPCA-1 cells (Fig. 1B,C). When compared with cells transfected with negative control mimic (RIBOBIO), cells transfected with miR137 mimic yielded a significant decrease of NSCLC cell growth after 72 h. Additionally, the proportion of cells at G0/G1 phase increased by >10% compared with the control 48 h post-transfection with miR-137 mimic (Fig. 1D). These results demonstrated that miR-137 could inhibit the proliferation of NSCLC cells and cause G0/G1 cell cycle arrest. Next, we used TargetScan prediction programs (www.targetscan. org) to identify and propose ULK2 and IBTK as the potential targets for miR-137. ULK2 can act upstream of phosphatidylinositol