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 design of a multiple drug combination for treating stage 4 bladder cancer depends on a strategy of inhibiting the highly expressed genes ADRM1, COPS5, PSMD8, SUMO2, RNF126, CALR, PDIA3, DNAJB11, HSPA5, RPN1, HSP90AA1, HSPA1B, METTL23, RARRES3, KPNA2, PSMD12, ECT2, JUN, TK1, TUBA1C, HN1, and ENO1; activating the suppressed genes BCL3, FOS, UBC, and GTF2A1; and suppressing the drug's effect on the nondifferentially expressed genes, which are the same as those in stage 1 bladder cancer.
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.
The epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), and heat shock protein A member 5 (HSPA5) were the top three hubs, indicating highest connectivity and greatest capacity to regulate the interaction network (Figures 4 and 5).
Quantitative PCR was performed to confirm expression changes of proteins with highest connectivity, including EGFR, TP53, HSPA5, excision repair cross-complementation group 1 (ERCC1), and X-ray repair cross complementing 1 (XRCC1), in several prostate cell lines.
HSPA5 is also overexpressed in some cancers, including breast, hepatocellular, and lung cancer [23-25].
Tseng et al., "De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells," Oncotarget, vol.