TES functions as a Mena‐dependent tumor suppressor in gastric cancer carcinogenesis and metastasis

Abstract

BackgroundIn our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC.MethodsWe explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC.ResultsTES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P = 0.005), lymph node metastasis (P = 0.003), TNM stage (P = 0.003), and prognosis (P = 0.010). However, no significant association was observed in GC patients with low Mena expression.ConclusionsWe believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.Electronic supplementary materialThe online version of this article (10.1186/s40880-019-0347-y) contains supplementary material, which is available to authorized users.

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“…Downregulation or loss of NDUFA1 expression is a known consistent feature of basal cell carcinoma ( Mamelak et al, 2005 ), while reduced expression of IL13RA1 has been associated with apoptosis and promotion of epithelial to mesenchymal transition (EMT) in pancreatic cancer ( Shi et al, 2022 ). Like OSR1 , TES (testin LIM domain protein) functions as a Mena-dependent tumour suppressor gene in many cancers, including gastric cancer ( Wang et al, 2019 ), with loss of expression associated with cancer progression. However, TES overexpression has been noted in progressive cervical intraepithelial neoplasia ( Popiel et al, 2021 ).…”

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“…More importantly, we found that knockdown of NAT10 increased the expression levels of miR-9-5p targets, including SH3BP4, NCOR2, LMNA, EPAS1 and TES (NEW Fig. S7 a), which exhibit tumor suppressive properties [ 65 – 68 ]. Therefore, we believe that some miR-9-5p targets may play a role in regulating tumorigenesis after NAT10 knockdown.…”

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“…ENO3 is a gene involved in the glycolytic pathway, but seemingly contributes to improved prognosis, with lower levels associated with worse survival in pancreatic cancer [142,143,145]. With respect to TES, while it has been reported to act as a tumor suppressor in other tumor types [146,147], in pancreatic cancer its increased expression seems to be associated with worse survival [143,144].…”