Introduction

Esophageal cancer (EC) is the sixth most prevalently diagnosed malignancy in the world with estimated 450,000 deaths every year. Strikingly, China accounts for half of the global morbidity as well as mortality of EC [1, 2]. Esophageal squamous cell carcinoma (ESCC), as well as esophageal adenocarcinoma (EAC), is the primary histological types of EC. In China, ESCC is the most predominant subtype with high incidences, accounting for 90% of newly diagnosed EC cases [3, 6]. Recently, Zhong et al. reported that TAB182 is up-regulated in lung adenocarcinoma and affects lung adenocarcinoma cells’ sensitivity to DNA damage regent through regulating the homologous recombination pathway of DNA double-strand breaks (DSB) [7]. Moreover, Zhou and colleagues found that TAB182 could be induced by ionizing radiation (IR), and TAB182 is required for the efficient repair of IR-mediated DSB through enhancing DNA-PKcs’ interacting with PARP-1 [8]. Our previous study showed that TAB182 heightens the radioresistance of ESCC cells by mediating the G2-M checkpoint via its interaction with FHL2 [9]. Although recent studies have revealed the crucial roles of TAB182 in DNA damage response, whether and how TAB182 associates with ESCC tumorigenesis and progression remain unclear.

FHL2 is a multifunctional scaffolding protein that belongs to the four-and-a-half LIM domains protein family. FHL2 has been found to interact with multiple types of proteins due to its unique structure that consists of several LIM motifs, including IER3 and MDM2 [10], EGFR, and EGFRvIII [11]. Additionally, it is reported that the zinc-finger motif in the LIM domain confers FHL2 with transcriptional repressor or co-activator function [12, 13]. As a result, FHL2 is involved in the modulation of varied cellular processes, including gene expression, cell proliferation and motility [14]. Interestingly, accumulating evidence has demonstrated the critical roles of FHL2 in tumorigenesis and the progression of carcinoma in a context-dependent manner. For instance, it exerts oncogenic function in ovarian cancer [15], cervical cancer [10], and gastrointestinal cancer [28], suggesting that TAB182 may act differently in different types of cancer cells.

Tumorigenesis and tumor malignant nature are often associated with cancer cell stemness. ESCC cells with cancer stem cells characteristics have been considered to more inclined to distant metastasis, resulting in poor prognosis of the patients [29]. Here, we discovered that TAB182 promotes the stemness and tumorigenicity of ESCC cells by triggering the nucleus translocation of β-catenin to stimulate the β-catenin pathway, which leads to the activated transcription of JUN, MYC, ALDH1A1, CD44, and CD133. In accordance with our findings, Huang revealed that the activation of β-catenin signaling enhances the androgen-independent self-renewal of ESCC cells with stem cell-like characteristics [30]. While the molecular processes underlying the modulation of β-catenin by TAB182 in ESCC remain to be further elucidated, we discovered that TAB182 physically interacts with β-catenin and prevents it from being phosphorylated by GSK3β and ubiquitination-mediated degradation. TAB182 further recruits FHL2 and forms a TAB182-FHL2-β-catenin complex allowing for efficient FHL2-mediated β-catenin nucleus translocation by enhancing the association between FHL2 and β-catenin, and this is dependent on the RXXPDG motif of TAB182 in ESCC cells. These findings indicated that TAB182 may serve as a crucial malignant factor and novel stemness-related modulator via the TAB182-FHL2-β-catenin axis in ESCC.

Conclusions

In summary, our study reveals the novel oncogenic role of TAB182 in ESCC and avail useful insights into a probable function of the TAB182/FHL2/β-catenin molecular axis in ESCC cell stemness, invasiveness, and tumorigenicity. Of clinical relevance, TAB182 might function as a potential diagnostic marker for ESCC. Additionally, targeting the TAB182/FHL2/β-catenin can be a new avenue for the development of therapeutics against ESCC.