背景:男性结直肠癌(CRC)的发病率和死亡率持续高于女性。CRC恶性程度受到小的非编码RNA(miRNA)的强烈影响。此外,昼夜节律分子振荡器的失调与CRC的促进有关。为了分析上述因素对CRC进展的可能累积影响,我们关注与clock基因per2和/或cry2相关的性别偏倚miRNA的功能,这些miRNA参与细胞周期控制和DNA损伤反应.
结果:我们鉴定了miR-24,miR-92a,miR-181a,与per2相关的miR-21在男性转化的结肠组织中上调。miR-93,miR-17,miR-20a,男性表达高于女性的miR-24与cry2相关。所有这些miRNA都具有致癌潜力,并主要通过抑制肿瘤抑制因子磷酸酶和张力蛋白同源物(PTEN)和/或p53发挥其作用。通过抑制肿瘤抑制因子per2,男性中PTEN和p53的下调得到了进一步加强。在女性的转化结肠组织中未检测到与per2或cry2相关的致癌上调miRNA。
结论:我们得出结论,性别偏向miRNAmiR-24,miR-92a,miR-181a,miR-93,miR-17,miR-20a,与时钟基因per2和/或cry2相关的miR-21可以通过抑制PTEN和p53途径促进CRC的性别依赖性发展。
BACKGROUND: The incidence and mortality of colorectal cancer (CRC) are persistently higher in men than in women. CRC malignancy is strongly influenced by small non-coding RNAs (miRNAs). Moreover, deregulation of the circadian molecular oscillator has been associated with CRC facilitation. To analyse possible cumulative effects of the above-mentioned factors on CRC progression, we focused on functions of sex-biased miRNAs associated with the clock genes
per2 and/or cry2, which are involved in the cell cycle control and DNA damage response.
RESULTS: We identified miR-24, miR-92a, miR-181a, and miR-21 associated with
per2 that are up-regulated in transformed colon tissue of men. miR-93, miR-17, miR-20a, and miR-24 with higher expression in males compared to females were linked to cry2. All these miRNAs possess oncogenic potential and exert their effects mainly via inhibition of the tumour suppressors phosphatase and tensin homolog (PTEN) and/or p53. Down-regulation of PTEN and p53 in men was further strengthened by inhibition of tumour suppressor
per2. Oncogenic up-regulated miRNAs associated with
per2 or cry2 in the transformed colon tissue of women were not detected.
CONCLUSIONS: We conclude that the cancer-promoting, sex-biased miRNAs miR-24, miR-92a, miR-181a, miR-93, miR-17, miR-20a, and miR-21 associated with clock genes
per2 and/or cry2 can contribute to the sex-dependent development of CRC via inhibition of the PTEN and p53 pathways.