Gastric carcinoma still threatens public health with higher morbidity and mortality, especially in Eastern Asia, Eastern Europe, and South Africa [2, 28]. Recently target therapy represents a vast value and made great progress in cancer treatment, such as in lung adenocarcinoma and colorectal adenocarcinoma [29, 30]. However, up to now, excepting the most major target-HER2 and VEGF/VEGFR, other target options,including EGFR and HGF/MET, have emerged but not been proved effective in prolonging the survival time. The homodimers or heterodimers formed in HER family pairs can activate MAPK, PI3K and other signaling pathways, thereby regulating cell proliferation, adhesion, migration, and differentiation [31, 32]. Trastuzumab is a type of anti-HER-2 drug that binds to the extracellular domain IV of HER2 and inhibits homodimers' formation. It has shown beneficial in survival, combined with cisplatin and a fluoropyrimidine, for the treatment of gastric carcinoma patients with HER2 positive expression . Remizumab is a type of monoclonal antibody and can bind to extracellular domain of VEGFR-2 to suppress angiogenesis. Clinical trial demonstrated that it effectively prolonged survival time when combined with chemotherapy for patients with advanced gastric carcinoma . Cetuximab and Panitumumab are also anti-EGFR antibodies. Clinical trials stated that there had none improvement in survival rates for advanced gastric carcinoma when combined with Cetuximab, and Panitumumab not only failed in improving the survival time, but also increased toxicities [35–37]. Meanwhile, Rilotumumab, which can anti-HGF, could improve the prognosis for gastric cancer patients with higher expression of MET, but was proved a worse safety[38, 39].Depending on this circumstance, a string of targets and drugs are needed in gastric carcinoma.
Based on this GSEA analysis, which utilized multiple transcriptome data sets and CTD dataset, Bazedoxifene was found closely related with some specific genes which highly expressed in gastric carcinoma, and it may be a new drug for patients with gastric carcinoma. Bazedoxifene is the third-generation selective estrogen receptor modulator (SERM), which received FDA approval to prevent postmenopausal osteoporosis and moderate to severe vasomotor symptoms associated with menopause . It mainly targeted on estrogen receptor alpha (ESR1) and estrogen receptor alpha (ESR2), which are all nuclear hormone receptor and can activate the expression of reporter genes, containing estrogen response elements (ERE) .
Furthermore, some researches demonstrated that Bazedoxifene can be a novel and useful drug in cancer treatment. Jia et al found that Bazedoxifene significantly inhibit colorectal cancer cell proliferation and migration by blocking IL-11/GP130 signaling pathway in vivo and in vitro . SJW et al also demonstrated that Bazedoxifene is a novel inhibitor of GP130 signaling pathway, and it can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells . The study discovered that Bazedoxifene combined with paclitaxel exhibited more potent inhibition of cell viability, colony formation, and cell migration, induced more apoptosis in vitro, and generated stronger inhibition of tumor growth of breast cancer in vivo than either drug alone . Furthermore, a study also implied that it suppressed the development of hepatocellular carcinoma .
Interestingly, IL-11/GP130 and ERE related signaling pathway were related with the progression of gastric cancer. Some researches had identified that deregulation of gp130-dependent STAT1/STAT3 signal pathway, leading by the crucial cytokine IL-11, involved in the human Helicobacter pylori infection and pathogenesis of gastric cancer [46–48].it has been identified that decreasing of estrogen receptor binding affinity to the estrogen response element could decrease the expression of the TFF1 gene, which may be involved in development of gastric cancer.
In this study, it was shown that UHRF1 was a potential target site for Bazedoxifene in gastric carcinoma. As this study showed, it was screened as a hub-genes from the PPI network and identified as an apparent overexpressed gene and demonstrated a stable binding site for Bazedoxifene in protein level. UHRF1 is a nuclear protein gene involved in tumorigenesis and development. It encodes a member of a subfamily of RING-finger type E3 ubiquitin ligases. UHRF1 can participate in DNA methylation modification and histone post-translational modification through specific domains, regulate gene expression, and participate in malignant tumors' occurrence and development . That was consistent with our pathway analysis, which indicated that Bazedoxifene mainly targets ubiquitin-like protein transferase activity, ubiquitin-protein transferase activity, viral carcinogenesis MAPK pathway in gastric carcinoma. Meanwhile, UHRF1 is up-regulated in various cancers, including lung cancer, cervical cancer, pancreatic cancer, and so on.Researches reported that knocking down UHRF1 reduced tumor cell proliferation and promote apoptosis, so it is therefore considered to be a therapeutic target [50–53]. In gastric carcinoma, The UHRF1 expression in serum and tissue were significantly higher than health control and may represent a novel biomarker for diagnosis and prognosis . Meanwhile, Zhou L et al also reported that UHRF1 was overexpressed, and it was an independent and significant predictor. Moreover, downregulation of UHRF1 suppressed cell proliferation in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Also, UHRF1 overexpression promoted gastric carcinoma proliferation and carcinogenesis by inhibiting apoptosis and increasing the G1/S transition and inducing the hypermethylation of 7 tumor-suppress-genes (CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1, and PML) . Other research also indicated that UHRF1 could promote the growth, migration, and invasion of gastric carcinoma cells and inhibited apoptosis via a ROS-associated pathway . So, Bazedoxifene may act at UHRF1 to play a role in treating patients with gastric carcinoma.
Some other genes may also be targets for gastric carcinoma, including MCM10, HELLS, and DTL, as this study shown. MCM10 is a subtype of Minichromosome Maintenance proteins (MCM) family, and is essential for replication origin firing . MCM10 can combine with other proliferative markers, initiate DNA replication of cell cycle, thereby mediating cell proliferation, and recruit DNA polymerase-α and a catalytic subunit, preventing the damage of DNA . Moreover, MCM10 was overexpressed in a series of cancers, including pancreatic cancer, cervical cancer, and esophageal cancers. It promoted tumor progression and maybe a prognostic biomarker and potential therapeutic target . HELLS is the primary member of the SNF2 chromatin remodeling enzyme family, and is related to the processes of DNA replication, repair, recombination, and transcription, and involved in typically interacts with DNA methyltransferases . Besides that, HELLS also involved in cancer development, including hepatocellular carcinoma, head and neck cancer, lung cancer, and breast cancer [61, 62]. Then, DTL is identified as an adapter of E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response, and translesion DNA synthesis . It can enhance cancer cells' motility and proliferation through PDCD4 ubiquitin-dependent degradation to promote the development of cancers .