Abstract
The LIM-domain protein AJUBA has been reported to be involved in cell-cell adhesion, proliferation, migration and cell fate decision by acting as a scaffold or adaptor protein. We previously identified AJUBA as a putative cancer gene in esophageal squamous cell carcinoma (ESCC). However, the function and underlying mechanisms of AJUBA in ESCC remain largely unknown. In the present study, we detected AJUBA levels in ESCC tumor tissues and in corresponding adjacent non-tumor tissues by immunohistochemistry (IHC) and investigated the function and mechanism of AJUBA in ESCC cells. The IHC results showed that AJUBA levels were significantly higher in ESCC tissues compared with corresponding adjacent non-tumor tissues (P < 0.001). Both in vitro and in vivo experiments showed that AJUBA promoted cell growth and colony formation, inhibited cisplatin-induced apoptosis of ESCC cells, and promoted ESCC cell migration and invasion. RNA sequencing was used to reveal the oncogenic pathways of AJUBA that were involved, and MMP10 and MMP13 were identified as two of the downstream targets of AJUBA. Thus, AJUBA upregulates the levels of MMP10 and MMP13 by activating ERK1/2. Taken together, these findings revealed that AJUBA serves as oncogenic gene in ESCC and may serve as a new target for ESCC therapy.
Highlights
Esophageal cancer is the sixth leading cause of cancer death and the eighth most frequently diagnosed cancer worldwide [1, 2], and most esophageal cancer cases are esophageal squamous cell carcinoma [3]
When comparing the staining result of tumor tissues with their paired non-tumor tissues, 62% (37/60) of the tumor tissues exhibited increased AJUBA expression (Figure 1C). These results indicated that AJUBA was frequently overexpressed in esophageal squamous cell carcinoma (ESCC) tumor tissues
To investigate the molecular mechanism by which AJUBA promoted MMP10 and MMP13 expression in ESCC cells, we examined the effects of AJUBA on extracellular signal-regulated kinase 1/2 (ERK1/2) activation
Summary
Esophageal cancer is the sixth leading cause of cancer death and the eighth most frequently diagnosed cancer worldwide [1, 2], and most esophageal cancer cases are esophageal squamous cell carcinoma [3]. AJUBA family proteins (AJUBA, LIMD1 and WTIP) belong to the Zyxin/AJUBA family. These proteins are characterized by the conservation of three tandem C-terminal LIM domains and a unique N-terminal preLIM region, which includes a nuclear export signal (NES) [5]. AJUBA family proteins can function as negative regulators of the Hippo pathway, affecting cell proliferation and controlling tissue size [6, 7]. Increasing evidence, including the detection of AJUBA mutations in multiple human cancers such as ESCC [11, 12], cutaneous squamous cell carcinoma [13] and head and neck squamous cell carcinomas [14], suggests a role for AJUBA in tumorigenesis. Previous studies have primarily focused on the Drosophila homolog of AJUBA [6, 7, 15], and the role of AJUBA in human cancer development has been controversially reported [10, 16]
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