OCT4-mediated transcription confers oncogenic advantage for a subset of gastric tumors with poor clinical outcome.

Deregulated transcription programs and signaling pathways are the critical factors involved in the process of carcinogenesis. Signaling pathway-based classification of tumors is expected to pave the way for the development of targeted therapeutics. We investigated the OCT4-mediated transcription program in the gene expression profiles of 939 gastric tumor samples. A set of 84 genes showing positive correlation with the activation pattern of the available OCT4 gene sets were found to consistently express in diffuse, poorly differentiated, and stage-III gastric tumors with poor prognosis. We also developed stable OCT4-silenced gastric cancer cells and the resultant gene expression changes were investigated by genome-wide mRNA profiling. Functional genomic investigation of the genes downregulated in OCT4-silenced cells and the pathways co-activated with OCT4 gene set across gastric tumors revealed the positive association of dysregulated OCT4 with TGF-ß, GLI, PRC2/EzH2, Wnt, KRAS, STK33, and YAP signaling pathways in diffuse subtype gastric tumors. Elevated expression of OCT4 gene set was identified to represent the previously described EMT_UP as well as the GENOMICALLY STABLE subtypes of gastric tumors. Integrative genomic screening of the drug sensitivity of gastric cancer cells in correlation with the expression of OCT4 gene set across drug sensitivity databases revealed the inhibitors of tyrosine kinases, HDAC, and HSP90 to have a negative correlation and needs to be investigated for their potential therapeutic features for the subset of OCT4-activated gastric tumors. Thus, the subset of gastric tumors with OCT4 activation, the associated oncogenic signaling pathways, and potential therapeutic candidates were identified for the development of targeted therapeutic strategies.

Smart dual T1 MRI-optical imaging agent based on a rhodamine appended Fe(III)-catecholate complex.

A rhodamine appended Fe(iii)-catecholate complex Fe(RhoCat)3 is reported as a smart dual-modal T1 MRI-optical imaging probe. The high spin Fe(iii) coordination sphere and rhodamine unit act as MRI and optical reporters, respectively. The probe showed a r1-relaxivity of 4.37 mM-1 s-1 at 1.41 T via the interaction of second sphere water molecules to coordinated oxygen atoms. It produced an enhanced signal intensity of phantom images on the 7.0 T animal research MRI/MRS scanner at 25 °C and pH 7.3. The interaction of the probe with bovine serum albumin (BSA) significantly improved r1 relaxivity (7.09 mM-1 s-1). Moreover, the optical imaging reporter rhodamine moiety exhibited sensitivity towards biomolecule nitric oxide (NO) and acidic pH via the formation of a ring-opened tautomer of rhodamine, wherein the r1 relaxivity of the probe was enhanced to 5.19 mM-1 s-1 for NO and slightly decreased for acidic pH. Further, the probe visualized NO in adenocarcinoma gastric (AGS) cells via a turn-on fluorescence mechanism with 80% cell viability. Thus, Fe(RhoCat)3 is demonstrated as a potential dual "MRI-ON and Fluorescence-ON" molecular imaging probe to visualize the NO molecule and acidic pH in the tumour microenvironment.

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients.

The identification of new drugs for the targeted therapy of gastric cancer remains an important need. The RAS/RAF/MEK/ERK/ELK1 signaling cascade is activated in many cancers, including gastric cancer. To identify the targetable inhibitors of the ERK/MAPK pathway, we performed a repurposing screening of a panel of antimicrobial agents in gastric cancer cells using an ERK/MAPK-driven firefly luciferase reporter assay. Multiple antibiotics were identified to inhibit ERK-mediated transcriptional activity. Among them, doxycycline showed high inhibition of ERK/MAPK-regulated transcriptional activity and the levels of ERK proteins. Doxycycline was further identified to inhibit the proliferation and the colony- and spheroid-forming potential of gastric cancer cells. By in vitro signaling pathway and genome-wide expression profiling analyses, doxycycline was identified to inhibit signaling pathways and transcriptional activities regulated by ER, Myc, E2F1, Wnt, SMAD2/3/4, Notch, and OCT4. Doxycycline was also found to activate p53-, ATF6-, NRF1/2-, and MTF1-mediated transcription and inhibit the transcription of histones, proteasomal genes, fibroblast growth factor, and other oncogenic factors. These observations show the multitargeting and targeted therapeutic features of doxycycline for a subset of gastric tumors.