ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells

abstract: ...Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of ovarian cancer. ARHGAP10 is a member of RhoGAP proteins and inactivates Cdc42 by converting GTP-bound form to GDP-bound form. Here, we aimed to evaluate ARHGAP10 expression profile and functions in ovarian cancer. The decreased expression of ARHGAP10 was found in 77.3% (58/75) of ovarian cancer tissues, compared with their non-tumorous counterparts. Furthermore, overall survival in ovarian cancer patients with higher expression of ARHGAP10 was longer than those with lower expression. Ectopic expression of ARHGAP10 in two ovarian cancer cell lines with lower expression of ARHGAP10 (A2780 and HO-8910) dramatically suppressed cell proliferation in vitro . In nude mice, its stable overexpression significantly inhibited the tumorigenicity of A2780 cells. We further demonstrated that overexpression of ARHGAP10 significantly inhibited cell adhesion, migration and invasion, resulted in cell arrest in G1 phase of cell cycle and a significant increase of apoptosis. Moreover, ARHGAP10 interacted with Cdc42 and overexpression of ARHGAP10 inhibited the activity of Cdc42 in A2780 cells. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that KEGG cell cycle, replication and base excision repair (BER) pathways were correlatively with the ARHGAP10 expression, which was further confirmed in ovarian cancer cells by western blotting. Hence, ARHGAP10 may serve as a tumor suppressor through inactivating Cdc42, as well as inhibiting cell cycle, replication and BER pathways. Our data suggest an important role of ARHGAP10 in the molecular etiology of cancer and implicate the potential application of ARHGAP10 in cancer therapy.

...Cell Death Dis Cell Death Dis Cell Death & Disease 2041-4889 Nature Publishing Group 27010858 4823924 cddis2015401 10.1038/cddis.2015.401 Original Article ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells ARHGAP10 and ovarian tumorigenicity Luo N 1 2 Guo J 1 2 Chen L 1 2 Yang W 1 2 Qu X 1 2 Cheng Z 1 2 * 1 Department of Gynecology & Obstetrics, Yangpu Hospital, School of Medicine, Tongji University , Shanghai 200090, China 2 Institute of Gynecological

.../licenses/by/4.0/ Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of ovarian cancer. ARHGAP10 is a member of RhoGAP proteins and inactivates Cdc42 by converting GTP-bound form to GDP-bound form. Here, we aimed to evaluate ARHGAP10 expression profile and functions in ovarian cancer. The decreased expression of ARHGAP10 was found in 77.3% (58/75) of ovarian cancer tissues, compared with their non-tumorous counterparts. Furthermore, overall survival in ovarian cancer patients with higher expression of ARHGAP10 was longer than those with lower expression. Ectopic expression of ARHGAP10 in two ovarian cancer cell lines with lower expression of ARHGAP10 (A2780 and HO-8910) dramatically suppressed cell proliferation in vitro . In nude mice, its stable overexpression significantly inhibited the tumorigenicity of A2780 cells. We further demonstrated that overexpression of ARHGAP10 significantly inhibited cell adhesion, migration and invasion, resulted in cell arrest in G1 phase of cell cycle and a significant increase of apoptosis. Moreover, ARHGAP10 interacted with Cdc42 and overexpression of ARHGAP10 inhibited the activity of Cdc42 in A2780 cells. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that KEGG cell cycle, replication and base excision repair (BER) pathways were correlatively with the ARHGAP10 expression, which was further confirmed in ovarian cancer cells by western blotting. Hence, ARHGAP10 may serve as a tumor suppressor through inactivating Cdc42, as well as inhibiting cell cycle, replication and BER pathways. Our data suggest an important role of ARHGAP10 in the molecular etiology of cancer and implicate the potential application of ARHGAP10 in cancer therapy. Rho GTPases act as key regulators of various cell functions, including cell cytoskeleton organization, migration, gene transcription, adhesion, cell proliferation and survival. 1 ARHGAP10 (also known as ARHGAP21) is an important member of Rho GTPase-activating proteins (RhoGAP), 2 which catalyze the conversion of active GTP-bound Rho GTPases to the inactive GDP-bound form, and thus suppress Rho GTPases-mediated cellular processes. In addition to its RhoGAP domain, ARHGAP10 contains a PDZ and a pleckstrin homology domain. Besides serving as a RhoGAP for Cdc42, 3 RhoA and RhoC, 4 ARHGAP10 can also interact with several proteins, including -catenin, 5 ARF1, 3 FAK, PKC- 6 and -arrestin 1, 7 and thus is involved in various cell functions, such as cell junction formation, 5 vesicular trafficking of Golgi membranes, 3 cardiac stress, 6 influenza virus replication 8 and stress fiber formation. 7 Recently, methylation and single nucleotide polymorphisms of ARHGAP10 have been described in pediatric leukemia 9 and invasive breast cancer, 10 respectively, which indicated the association of ARHGAP10 and cancer. Ovarian cancer is the most lethal gynecologic malignancy. 11 In spite of advances in surgery, radiation and chemotherapy, the overall survival of

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Gene: ARHGAP10 - Rho GTPase activating protein 10 - (NCBI)

Protein : 2mio

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