J Cancer 2021; 12(15):4616-4625. doi:10.7150/jca.56014

Research Paper

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

Sung-Hwa Sohn1*, Hee Jung Sul1*, Bohyun Kim1, Hyeong Su Kim2, Bum Jun Kim2, Hyun Lim2, Ho Suk Kang2, Jae Seung Soh2, Kab Choong Kim3, Ji Woong Cho3, Jinwon Seo4, Youngho Koh5, Dae Young Zang1,2✉

1. Hallym Translational Research Institute, Hallym University Sacred Heart Hospital, Anyang, 14066, Republic of Korea.
2. Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea.
3. Department of Surgery, Hallym University Medical Center, Hallym University Kangnam Sacred Hospital, Singil-ro Yeongdeungpo-gu, Seoul, 07441, Republic of Korea.
4. Department of Pathology, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do 14068, Republic of Korea.
5. Department of Bio-medical Gerontology, Ilsong Institute of Life Sciences, Hallym University, Anyang, Gyeonggi-do, Republic of Korea.
*The authors contributed equally to this work.

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Citation:
Sohn SH, Sul HJ, Kim B, Kim HS, Kim BJ, Lim H, Kang HS, Soh JS, Kim KC, Cho JW, Seo J, Koh Y, Zang DY. RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer. J Cancer 2021; 12(15):4616-4625. doi:10.7150/jca.56014. Available from https://www.jcancer.org/v12p4616.htm

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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.

Keywords: gastric cancer, PWWP2B, RNF43, docetaxel trihydrate, pelitinib, uprosertib