title: ADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation.
abstract: A disintegrin and metalloproteinase-17 (ADAM17) can cut and release a wide variety of epidermal growth factor receptor (EGFR) ligands to promote survival, invasion and proliferation of cancer cell, and therefore, is considered to be a potential therapeutic target for cancer. The main goal of the present study was to observe the effects of ADAM17 small interfering RNA (ADAM17-siRNA) on human MCF-7 breast cancer and investigate its activation pathway. In vitro, MCF-7 cells were divided into ADAM17-siRNA groups, nonsense siRNA groups, AG1478 (selective EGFR blocker) groups, LY294002 [phosphatidylinositol 3-kinase (PI3K) phosphorylation inhibitor] groups, PD0325901 [mitogen extracellular kinase (MEK) inhibitor] groups and control groups. In vivo, MCF-7 cells were implanted subcutaneously into nude mice and then these mice were randomly divided into ADAM17-siRNA groups, vector groups and control groups. Our data showed that compared with the control groups, ADAM17-siRNA, AG1478 and LY294002 could inhibit the migration and proliferation of MCF-7 cells, but PD0325901 and nonsense siRNA did not show this effect. Except that specific ADAM17-siRNA could inhibit the expression of ADAM17 mRNA, others did not change it. Western blot analysis further confirmed that EGFR-PI3K-AKT signaling pathway is involved in ADAM17-siRNA inhibiting migration and proliferation of MCF-7 cells. Similarly to the former, the growth of MCF-7 breast cancer in nude mice was significantly inhibited by ADAM17-siRNA. Compared with the control group and the vector group, the tumor volume was smaller in the ADAM17-siRNA group, the tissues developed large areas of necrosis, immunohistochemistry showed low expressions of ADAM17 and Ki-67 and western blot analysis proved that the expression of ADAM17 protein in the tissue was also reduced. The present study suggests that ADAM17-siRNA inhibits MCF-7 breast cancer and is activated through the EGFR-PI3K-AKT signaling pathway.
authors.affiliation: Department of Surgical Oncology, Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Xiangchao
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Surgical Oncology, Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Hu
authors.affiliation: International Education College, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Mohammad Monir
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: Department of Surgical Oncology, Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Guofu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pathology, Basic Scientific Medical College, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Surgical Oncology, Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China.
authors.forename: Xuepeng
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000072198:ADAM17 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002867:Chromones / Q000008:administration & dosage; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D011799:Quinazolines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506614:mirdametinib; D004159:Diphenylamine; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human