RNA interference (RNAi) acts constitutively to silence the innate immune response, and innate immunity genes are misregulated in Dicer-deficient Caenorhabditis elegans. Here, we show that inhibition of Dicer expression by RNAi in human cells up-regulates major histocompatibility complex class I–related molecules A and B (MICA and MICB). MICA and MICB are innate immune system ligands for the NKG2D receptor expressed by natural killer cells and activated CD8(+)T cells. We reveal that knockdown of Dicer elicits DNA damage. Up-regulation of MICA and MICB by Dicer knockdown is prevented by pharmacologic or genetic inhibition of DNA damage pathway components, including ataxia telangiectasia mutated (ATM) kinase, ATM- and Rad3-related kinase, or checkpoint kinase 1. Therefore we conclude that up-regulation of MICA and MICB is the result of DNA damage response activation caused by Dicer knockdown. Our results suggest that RNAi is indirectly linked to the human innate immune system via the DNA damage pathway.

Dicer, the key enzyme in the RNAi pathway, is misregulated in tumor tissues. The altered expression of Dicer is associated with clinical characteristics in patients with cancer. Liver carcinoma and adjacent non-neoplastic tissues were obtained from 36 patients with hepatocellular carcinoma (HCC) undergoing surgery. Expressions of Dicer mRNA were evaluated using the Real-time reverse transcription-PCR in 36 liver carcinoma tissues and 36 adjacent histologically non-cancerous liver tissues. Dicer mRNA levels were evaluated in relation to age, sex, tumor number, tumor size, tumor stage, and distant metastasis. Dicer mRNA level was significantly lower in malignant tissues than in the corresponding non-neoplastic tissues in 34 of the 36 patients with HCC (94.4%). The Dicer expression level was not associated with clinical characteristics, including age, sex, tumor number, tumor size, tumor stage, or distant metastasis in HCC cases. These results demonstrate that Dicer is significantly down-regulated in HCC, suggesting that reduced expression of Dicer may play an important role during the process of hepatocarcinogenesis.

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These data indicated that pSUPER-BCRPs could modulate MDR and may present a new approach to overcome BCRP-mediated drug resistance in HEPG2/ADM cells. It may reverse multidrug resistance phenotype and therefore provide promising therapeutic modalities in the treatment of hepatocellular carcinoma.