Seungkyung Kang1, Miree Park2, Jung Yeon Cho2, Su Jin Ahn3, Changhwan Yoon4, Sang Gyun Kim1, Soo-Jeong Cho5. 1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. 2. Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. 3. Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. 4. Department of Surgery, Columbia University Irving Medical Center, 630 W. 168th St, New York, NY, 10032, USA. 5. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. crystal522@daum.net.
Abstract
BACKGROUND: Diffuse-type gastric cancer (DGC), for which Helicobacter pylori infection is a causal factor, is associated with poor prognosis among young women, possibly due to female hormones such as estrogen. We aimed to identify the carcinogenesis induced by estrogen and H. pylori in DGC. METHODS: We screened and selected estrogen receptor alpha (ERα)-positive (MKN45) and ERα-negative (SNU5) DGC cell lines. H. pylori strain 60190 and its isogenic mutant strain lacking cytotoxin-associated gene A (60190ΔCagA) were used to infect MKN45 cells. And the cytotoxin-related gene A (CagA) cDNA which was cloned into pSP65-SR-HA (cagA-pSP65SRa) vector was used to transfect MKN45 cells. Tumor samples were used for DGC organoid culture. RESULTS: In MKN45 cells, we found that estradiol promotes epithelial-mesenchymal transition (EMT) and stemness phenotypes via HOTAIR expression. These effects were further enhanced by the addition of CagA secreted by H. pylori but were reversed by co-treatment with fulvestrant (ICI 182,780), a selective ER degrader. We also validated the effect of estrogen on DGC organoids. ERα expression was associated with tumor invasion and HOTAIR expression in DGC patients with overt H. pylori infection. CONCLUSIONS: These findings may explain the rapid DGC progression in young women with physiologically high levels of estrogen and suggest that fulvestrant with ovarian function suppression could serve as a tumor-suppressive agent in premenopausal patients with DGC.
BACKGROUND: Diffuse-type gastric cancer (DGC), for which Helicobacter pylori infection is a causal factor, is associated with poor prognosis among young women, possibly due to female hormones such as estrogen. We aimed to identify the carcinogenesis induced by estrogen and H. pylori in DGC. METHODS: We screened and selected estrogen receptor alpha (ERα)-positive (MKN45) and ERα-negative (SNU5) DGC cell lines. H. pylori strain 60190 and its isogenic mutant strain lacking cytotoxin-associated gene A (60190ΔCagA) were used to infect MKN45 cells. And the cytotoxin-related gene A (CagA) cDNA which was cloned into pSP65-SR-HA (cagA-pSP65SRa) vector was used to transfect MKN45 cells. Tumor samples were used for DGC organoid culture. RESULTS: In MKN45 cells, we found that estradiol promotes epithelial-mesenchymal transition (EMT) and stemness phenotypes via HOTAIR expression. These effects were further enhanced by the addition of CagA secreted by H. pylori but were reversed by co-treatment with fulvestrant (ICI 182,780), a selective ER degrader. We also validated the effect of estrogen on DGC organoids. ERα expression was associated with tumor invasion and HOTAIR expression in DGC patients with overt H. pylori infection. CONCLUSIONS: These findings may explain the rapid DGC progression in young women with physiologically high levels of estrogen and suggest that fulvestrant with ovarian function suppression could serve as a tumor-suppressive agent in premenopausal patients with DGC.
Authors: Brian De; Ryan Rhome; Vikram Jairam; Umut Özbek; Randall F Holcombe; Michael Buckstein; Celina Ang Journal: Gastric Cancer Date: 2018-04-24 Impact factor: 7.370
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702
Authors: Eun Jeong Gong; Ji Young Lee; Suh Eun Bae; Young Soo Park; Kee Don Choi; Ho June Song; Gin Hyug Lee; Hwoon-Yong Jung; Woo Jin Jeong; Gab Jin Cheon; Jeong Hwan Yook; Byung Sik Kim Journal: PLoS One Date: 2018-04-05 Impact factor: 3.240