Mechanism for the selection of anti-cancer networks by tumor-suppressive miRNAs

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By detailed analysis of miR-101 and miR-22, we successfully found novel intra-cellular networks, which are deeply involved in the regulation of cancer cell proliferation. miR-101 was defined as a novel regulator for G2 checkpoint of cell cycle through the repression of several microtubule regulators, and resulted in its function as a inducer of p53-dependent apoptosis. We also confirmed that expression of miR-101 is frequently down-regulated in human cancers.We identified NEK9 as a crucial regulator for cell cycle progression in p53-inactivated cancer cells through the target screening of miR-22. Knockdown of NEK9 was caused to repress cell proliferation only in p53 mutant and deficient cells both in vitro and in vivo. NEK9 KD was indicated to induce prolonged inhibition of G1 to S progression of cell cycle leading to express senescence-like features of cancer cells. Our findings might provide a novel strategy for cancer therapy targeting mutant p53.