Discussion

IQGAP2, part of the IQGAP family of scaffold proteins, has emerged as a significant tumor suppressor in multiple cancer types. Unlike its homolog IQGAP1, which often promotes tumor progression, IQGAP2 generally inhibits cancer cell proliferation, migration, and invasion, marking it as a promising molecular target for cancer therapy (White et al., 2009; White et al., 2010).

Our findings revealed a significant downregulation of IQGAP2 in ESCC tumor tissues, which is consistent with many reports that identified the downregulation of IQGAP2 across cancers. For example, a consistent finding in cancer research is the downregulation or loss of IQGAP2 expression in tumors. In hepatocellular carcinoma, IQGAP2 expression is frequently reduced, and this reduction correlates with enhanced tumor growth and poor prognosis (White et al., 2009). Functional studies in hepatocellular carcinoma models reveal that IQGAP2 deficiency leads to activation of oncogenic pathways, promoting cell proliferation and metastasis.

Similarly, prostate cancer exhibits decreased IQGAP2 levels, where loss of IQGAP2 is associated with aggressive tumor features (Xie et al., 2012). Restoration of IQGAP2 suppresses prostate cancer cell proliferation and migration, supporting its role as a tumor suppressor. In gastric cancer, reduced IQGAP2 expression correlates with advanced disease and worse survival outcomes (Jin et al., 2008; Xu et al., 2020).

IQGAP2 exerts tumor-suppressive effects through modulation of key signaling pathways. One well-studied mechanism is its inhibition of the Wnt/β-catenin pathway, a critical driver of tumorigenesis. In ovarian cancer, IQGAP2 suppresses Wnt/β-catenin signaling by reducing nuclear β-catenin translocation and transcriptional activity (Deng et al., 2016). This inhibitory effect is crucial in preventing uncontrolled cell proliferation and tumor progression.

IQGAP2 also negatively regulates the MAPK/ERK pathway, which is essential for cell growth and survival in many cancers. It has been demonstrated that overexpression of IQGAP2 inhibits phosphorylation of MEK and ERK, key components of this pathway, thereby suppressing tumor cell proliferation. In bladder cancer, it was shown that reduced IQGAP2 expression promotes epithelial–mesenchymal transition and tumor progression via activation of the MAPK/ERK pathway. Conversely, restoration of IQGAP2 impaired cell growth and lowered ERK phosphorylation levels (Song et al., 2022). Similarly, in breast cancer, Kumar et al. reported that overexpression of IQGAP2 led to a marked decrease in p-MEK and p-ERK, whereas knockdown enhanced ERK phosphorylation (Kumar et al., 2021). This regulation was shown to control cancer cell invasion and survival. These results align with our results in ESCC, where IQGAP2 reduces MEK/ERK activation, indicating a conserved role across tumor types. Together, these studies provide strong evidence that IQGAP2 plays a tumor-suppressive role by inhibiting the MAPK/ERK signaling cascade, making it a compelling candidate for targeted cancer therapies.

Epigenetic silencing of IQGAP2 through promoter methylation has been identified as a mechanism by which cancer cells downregulate its expression. In ovarian cancer, Deng et al. showed that methylation-mediated IQGAP2 silencing leads to activation of Wnt/β-catenin signaling and enhanced tumor growth, highlighting the clinical relevance of restoring IQGAP2 expression (Deng et al., 2016).

In bladder cancer, low IQGAP2 levels are associated with increased invasion and metastasis, supporting its suppressive role in tumor progression (Song et al., 2022). These findings emphasize IQGAP2’s broad tumor suppressor function mediated by common signaling pathways affected in various malignancies.

Clinically, IQGAP2 expression has prognostic significance; low IQGAP2 correlates with poor outcomes and more advanced disease stages in gastric, prostate, and liver cancers (White et al., 2010; Xie et al., 2019; Tang et al., 2021). This positions IQGAP2 as a potential biomarker for cancer prognosis. Therapeutically, targeting the pathways regulated by IQGAP2 or reversing its epigenetic silencing may provide new avenues for cancer treatment. Drugs aiming to demethylate the IQGAP2 promoter or mimicking its function could inhibit oncogenic signaling cascades such as Wnt/β-catenin and MAPK/ERK pathways. Further preclinical and clinical studies are needed to explore these strategies and validate IQGAP2’s utility as a therapeutic target.

Limitations of this study include its reliance on in vitro models, which, while informative, do not fully recapitulate the tumor microenvironment or systemic factors influencing ESCC progression. We acknowledge that in vivo validation using xenograft models is necessary to further confirm the tumor-suppressive role of IQGAP2. Such studies have not been performed in the present work but represent an important direction for future investigation. Additionally, exploring the prognostic value of IQGAP2 expression in ESCC could aid in patient stratification and personalized therapy development.