Yingying Liao1, Wei Chen2, Wei Shi3, Huolong Zha4. 1. Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Maojian District, Chaoyangzhong Road 39, Shiyan, 442000, Hubei, China. 2. Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China. 3. Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Maojian District, Chaoyangzhong Road 39, Shiyan, 442000, Hubei, China. rena13636170177@sina.com. 4. Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Maojian District, Chaoyangzhong Road 39, Shiyan, 442000, Hubei, China. 277570185@qq.com.
Abstract
BACKGROUND: Cytosolic phospholipase A2alpha (cPLA2α), an enzyme that is responsible for the hydrolysis of membrane phospholipids, is a key mediator of tumor transformation, progression and metastasis. The role of cPLA2α in gastric cancer has not been revealed. METHODS: cPLA2α expression was analyzed using RT-PCR and immunohistochemistry approaches in gastric cancer patient samples (n = 26) and multiple cell lines (n = 7). cPLA2α function was studied using plasmid overexpression and siRNA knockdown approaches in SNU-1, MKN-74 and MKN-45 cell lines. The downstream effectors of cPLA2α were determined using biochemical assays. RESULTS: cPLA2α upregulation is a common feature in gastric cancer patients, particularly those with metastasis. cPLA2α overexpression is sufficient to promote gastric cancer cell growth and migration, and confer chemo-resistance. cPLA2α depletion is active against gastric cancer via inhibiting growth and migration, and inducing apoptosis in gastric cancer cells. Of note, cPLA2α depletion augments efficacy of chemotherapy. Mechanistic studies confirm that cPLA2α regulates gastric cancer biological activities via mainly regulating Ras/MEK/ERK and possibly Akt/β-catenin pathways. Pearson correlation coefficient analysis also suggests a moderate positive correlation between cPLA2α and RAS in gastric cancer. CONCLUSIONS: Our work demonstrates cPLA2α inhibition as a therapeutic strategy to overcome chemo-resistance and highlights the association of cPLA2α and Ras in gastric cancer.
BACKGROUND: Cytosolic phospholipase A2alpha (cPLA2α), an enzyme that is responsible for the hydrolysis of membrane phospholipids, is a key mediator of tumor transformation, progression and metastasis. The role of cPLA2α in gastric cancer has not been revealed. METHODS: cPLA2α expression was analyzed using RT-PCR and immunohistochemistry approaches in gastric cancerpatient samples (n = 26) and multiple cell lines (n = 7). cPLA2α function was studied using plasmid overexpression and siRNA knockdown approaches in SNU-1, MKN-74 and MKN-45 cell lines. The downstream effectors of cPLA2α were determined using biochemical assays. RESULTS: cPLA2α upregulation is a common feature in gastric cancerpatients, particularly those with metastasis. cPLA2α overexpression is sufficient to promote gastric cancer cell growth and migration, and confer chemo-resistance. cPLA2α depletion is active against gastric cancer via inhibiting growth and migration, and inducing apoptosis in gastric cancer cells. Of note, cPLA2α depletion augments efficacy of chemotherapy. Mechanistic studies confirm that cPLA2α regulates gastric cancer biological activities via mainly regulating Ras/MEK/ERK and possibly Akt/β-catenin pathways. Pearson correlation coefficient analysis also suggests a moderate positive correlation between cPLA2α and RAS in gastric cancer. CONCLUSIONS: Our work demonstrates cPLA2α inhibition as a therapeutic strategy to overcome chemo-resistance and highlights the association of cPLA2α and Ras in gastric cancer.
Authors: Manish I Patel; Jaskirat Singh; Marzieh Niknami; Caroline Kurek; Mu Yao; Sasa Lu; Fiona Maclean; Nicholas J C King; Michael H Gelb; Kieran F Scott; Pamela J Russell; John Boulas; Qihan Dong Journal: Clin Cancer Res Date: 2008-12-15 Impact factor: 12.531
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