JWA loss promotes cell migration and cytoskeletal rearrangement by affecting HER2 expression and identifies a high-risk subgroup of HER2-positive gastric carcinoma patients

Abstract

Background and AimsJWA, a microtubule-associated protein (MAP) involved in apoptosis, has been identified as a suppressor of metastasis, and it affects cell migration in melanoma and its downregulation in tumor is an idependent negative prognostic factor in resectable gastric cancer. HER2 overexpression has been observed in gastric cancer (GC) cells and implicated in the metastatic phenotype. However, the biological role of JWA in migration and its clinical value in HER2-positive GC remain elusive.ResultsJWA suppresses EGF-induced cell migration and actin cytoskeletal rearrangement by abrogating HER2 expression and downstream PI3K/AKT signaling in HER2-overexpressing GC cell lines. The modulation of HER2 by JWA is dependent on ERK activation and consequent PEA3 upregulation and activation. Reduced JWA expression is associated with high HER2 expression and with poor survival in patients with AGC, whereas HER2 expression alone is not associated with survival. However, concomitant low JWA and high HER2 expression is associated with unfavorable outcomes. Additionally, when patients were stratified by JWA expression, those with higher HER2 expression in the low JWA expression subgroup exhibited worse survival.MethodsThe impact of JWA on the EGF-induced migration of HER2-positive GC cells was studied using transwell assays and G-LISA assays. Western blotting, real-time PCR, electrophoretic mobility shift assays and luciferase assays were utilized to investigate the mechanisms by which JWA affects HER2. The association of JWA with HER2 and its clinical value were further analyzed by IHC in 128 pairs of advanced gastric cancer (AGC) and adjacent normal tissue samples.ConclusionsThis study characterizes a novel mechanism for regulating cell motility in HER2-overexpressing GC cells involving JWA-mediated MEK/ERK/PEA3 signaling activation and HER2 downregulation. Furthermore, JWA may be a useful prognostic indicator for advanced GC and may help stratify HER2-positive patient subgroups to better identify unfavorable outcomes.

JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling

“…JWA gene is biologically conserved in evolution and involves several essential functions, including regulations of cell differentiation, DNA repair, cytoskeleton organization, and maintenance of the homeostasis of glucose and lipid metabolism 23 , 32 , 33 . The biological functions of the JWA are achieved largely by regulating the MAPK signaling pathway, which is essential for maintaining basic life activities in organisms 34 .…”

“…Patients with low expression of JWA in tumor tissues usually suffer worse survival than those with high expression 21 , 22 . JWA negatively regulates HER2 expression and inhibits cell proliferation and migration in human gastric cancer cells through transcription and ubiquitination-related mechanisms 23 , 24 . However, it is unclear whether JWA regulates HER2 expression in breast cancer cells.…”

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

“…Our previous studies have reported that JWA gene is not only conserved in evolution but has several essential functions, including regulations on cell differentiation, DNA repair, cytoskeleton organization, and metabolisms of sugar and lipid [17,28,29]. The biological functions of the JWA gene is achieved largely by regulating the MAPK signaling pathway, which is essential for maintaining basic life activities in organisms [30].…”

“…Patients with lower expression of JWA in tumor tissues usually suffer worse survival than those with higher expression [15,16]. JWA negatively regulates HER2 expression and inhibits cell proliferation and migration in human GC cells through transcription and ubiquitination related mechanisms [17,18]. However, the role of JWA in regulating HER2 expression and its underlying mechanism in BC have not been determined.…”

JWA suppresses the invasion of human breast carcinoma cells by downregulating the expression of CXCR4

“…Numerous studies have indicated that JWA is a tumor suppressor gene as its downregulation promotes the survival, migration, invasion, metastasis and angiogenesis of a variety of human cancer cells ( 14 , 16 – 18 , 20 , 21 , 25 – 27 ). Regarding breast cancers, we have previously shown that JWA enhances As 2 O 3 -induced apoptosis of MCF-7 cells ( 12 , 13 ).…”