Our results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5.
Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverses the stemness of CRC to overcome these obstacles.
MiR-200c was markedly downregulated in CRC tissues, whereas the protein expression of BMI1 in CRC tissues was upregulated compared with normal colon tissues.
In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK-3β/β-catenin/Zeb1/miR-200c axis, suggesting that Fas signaling-based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.
Overall, GREM1 expression in CRCs was lower than that of the matched normal mucosa, and GREM1 expression had a strong positive correlation with BMI1 and inverse correlations with EPHB2 and OLFM4.
In a validation cohort, serum Bmi-1 mRNA levels were significantly elevated in the colorectal cancer group and the adenoma group when compared with other groups.
In Asian cases, high expression of Bmi-1 was associated with poor OS in oesophageal carcinoma (HR=1.93, 95% CI 1.52-2.46), gastric cancer (HR=1.50, 95% CI 1.22-1.85), lung cancer (HR=1.73, 95% CI 1.05-2.85), cervical cancer (HR=2.80, 95% CI 2.26-3.47) and colorectal cancer (HR=3.36, 95% CI 2.19-5.15), rather than in breast cancer and HCC.
These data suggest that 74-85% of colorectal cancers express a Lgr5/Ascl2 associated signature and support the hypothesis that they derive from Lgr5(+)/Ascl2(+) crypt stem cells, not Bmi1(+) stem cells.
In conclusion, miR-218 plays a pivotal role in CRC development through inhibiting cell proliferation and cycle progression and promoting apoptosis by downregulating BMI-1.
Collectively, our current results suggest that USP22 may act as an oncogene in CRC as it positively regulates cell cycle via both BMI-1-mediated INK4a/ARF pathway and Akt signaling pathway.
Additionally, the oncogenic role of USP22 in the progression of CRC can be mechanistically linked with BMI-1, c-Myc, and cyclin D2, but not with p16INK4a and p14ARF.