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miR-223 affects different target genes at multiple cancers like Artemin (oesophageal carcinoma) (41), C/EBP[beta] (leukaemia) (42), E2F1 (leukaemia)(35), EPB41L3 (gastric cancer) (36), Fbxw7/Cdc4 (leukaemia, gastric cancer, oesophageal squamous cell carcinoma) (43,44), FOXOl (colorectal cancer cells) (45), HSP90B1 (osteosarcoma) (46), IGF1R (HeLa, leukemia and hepatoma cells) (37,47), SEPT6 (prostate cancer) (48), LM02 (Leukaemia/lymphoma) (42) and NFI-A (Leukaemia/lymphoma)(49).
In Figure 3, our results reveal that ADRM1 regulates KPNA2, which promotes proliferation, and is mediated by the aging-related proteins, HSP90B1, CALR, HSPA5, PDIA3, RPN1, and ECT2, the smoking-related proteins, HUWE1, HSPA5, and ECT2, and the epigenetic regulation of ENO1, HSP90B1, CALR, and PDIA3, through the SUP and ER signaling pathways.
The receptor ADRM1 signal triggers the signaling cascade from the smoking-related protein HUWE1 to the aging-related proteins HSP90B1 and RPS20 and the smoking-related TF COPS5.
In summary, aging and epigenetic regulation dominate bladder carcinogenesis through CALR, PDIA3, DNAJB11, HSPA5, RPN1, HSP90B1, KPNA2, ECT2, and PSMD11 and through COPS5, PSMD8, RNF126, CALR, PDIA3, HSP90B1, PSMD12, PSMD11, JUN, HN1, and ENO1, respectively.
The design of a multiple drug combination for treating stage 1 bladder cancer depends on a strategy of inhibiting the highly expressed genes ADRM1, COPS5, PSMD8, SUMO2, CALR, PDIA3, DNAJB11, HSPA5, RPN1, CUL1, HSP90B1, KPNA2, PSMD12, ECT2, TK1, TUBA1C, HN1, and ENO1; activating the suppressed genes UBC, JUN, RARRES3, and FOS; and suppressing the drug's effect on the nondifferentially expressed genes BAG6, HUWE1, PAAF1, PSMD10, FAF2, PCYT1A, and PSMD10.
The major factors, including downregulated miR12, the aging-related proteins, HSP90B1, CALR, HSPA5, PDIA3, RPN1, and ECT2, the smoking-related proteins, HUWE1, HSPA5, and ECT2, and the epigenetic regulation of ENO1, HSP90B1, CALR, and PDIA3, lead to the progression from normal bladder cells to stage 1 bladder cancer cells through the SUP and ER signaling pathways.
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- HSP70-like protein 1
- HSP90 beta
- Hsp90 heat-shock proteins
- HSPA Evolved