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RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer.

ABSTRACT: Background: Abnormal regulation of genes has been closely related to gastric cancer. The characterization of gastric cancer has necessitated the development of new therapeutics as well as the identification of prognostic markers to predict the response to novel drugs. In our study, we used RNA sequencing analyses to show that on gastric cancer tissues to identification of gastric cancer prognostic markers. We specifically chose to study RNF43 because it inhibits gastric cancer-related Wnt/β-catenin signaling by interacting with Wnt receptors. PWWP2B was chosen because it is a gene which is downregulated in gastric cancer. Methods: Utilizing RNA sequencing analysis, we evaluated the mRNA expression profile in gastric cancer patients. Also, we used HAP1 cells which is a human near-haploid cell line derived from the male chronic myelogenous leukemia cell line KBM-7. These cell line has one copy of each gene, ensuring the edited allele will not be masked by additional alleles. We investigated the screening of 1,449 FDA-approved drugs in HAP1, HAP1 RNF43 KO and HAP1 PWWP2B KO cells. RNA sequencing data reveals that RNF43 and PWWP2B expression were down-regulated in recurrence gastric cancer patients. Next, we investigated the anti-cancer effects of selected drugs in RNF43 and PWWP2B down-regulated MKN45 gastric cancer cells and xenograft model. Results: Among these FDA-approved drugs, three drugs (docetaxel trihydrate, pelitinib and uprosertib) showed strong inhibitory effects in RNF43 KO cells and PWWP2B KO cells. In MKN45 xenograft model, tumor volumes were significantly reduced in the docetaxel trihydrate, uprosertib or pelitinib-treated group. Our data demonstrated that RNF43 and PWWP2B are a biomarker that predict recurrence of gastric cancer. Conclusions: Our findings suggest that docetaxel trihydrate, uprosertib and pelitinib could be used as novel therapeutic agents for the prevention and treatment of gastric cancer with a decrease in RNF43 and PWWP2B expression.

SUBMITTER: Sohn SH

PROVIDER: S-EPMC8210561 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The inability of the adult human heart to regenerate lost or damaged myocardial tissue has created one of the most pressing public health dilemmas due to the devastating impact of heart failure. Our group and others have outlined several regulators of cardiomyocyte mitosis that may impact the regenerative capacity of the adult myocardium in mammals. Recently, we reported that the transcription factors Meis1 and Hoxb13 regulate postnatal cardiomyocyte cell cycle arrest, where concomitant deletion of both genes induced cardiomyocyte proliferation and myocardial regeneration following ischemic injury. These studies suggest that pharmacological targeting Meis1 and Hoxb13 transcriptional activity could be a viable path towards heart regeneration. Therefore, we performed an in-silico screen to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the published crystal structure of Meis1 and Hoxb13 bound to DNA. Our screen yielded several candidates based on binding profiles to either Meis1 DNA binding domain, Hoxb13 DNA binding domain, or the interface between Meis1 and Hoxb13, as well as safety and side effect profiles. Out of the shortlist of top hits, paromomycin and neomycin induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay, and disruption of DNA binding by EMSA. X-ray crystal structure revealed that both paromomycin and neomycin bind to Meis1 near the Hoxb13 interaction site where they interact with 3 out of the 5 Meis1 amino acids that participate in DNA-binding. The crystal structure also demonstrates that both drugs bind at the interface of Meis1 homodimer, therefore placing one of the Meis1 monomers in a position incompatible with DNA-binding. Importantly, administration of paromomycin-neomycin combination by intraperitoneal injection in mice induced cardiomyocyte proliferation, improved left ventricular (LV) systolic function and decreased scar formation in two models of ischemic reperfusion injury in mice. Finally, dual intravenous administration of the paromomycin-neomycin combination in Yorkshire pigs following cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved LV systolic function, and decreased scar formation. Collectively, we identified paromomycin and neomycin as FDA-approved drugs with therapeutic potential for induction of heart regeneration in humans.

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RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer.

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