Esophageal cancer (EC) is the seventh leading cause of cancer-related mortality around the world, with more than 470,000 new cases each year (Bray et al., 2024). It consists of two dominant pathological subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) (Deboever et al., 2024). In China, around 90 % of EC cases are ESCC, making it the prevalent pathological subtype (Liu et al., 2024b, Xi et al., 2023). Due to the lack of typical clinical symptoms, many patients are diagnosed at an advanced stage, with a five-year survival rate of metastatic patients less than 5 % (Wong et al., 2024). At current, chemotherapy (such as cisplatin (CDDP)) is one of the main treatment options for patients with advanced ESCC (Xu et al., 2024). Unfortunately, chemoresistance limits the treatment efficacy, and the disease-free survival rate is around 55–63.6 % within 5 years (Nakagawa et al., 2025, Yang et al., 2021). Furthermore, there are no effective treatment strategies for patients with recurrent ESCC. Therefore, metastasis and treatment resistance are the challenges that prevent ESCC patients from achieving long-term benefits from treatment (Zhang et al., 2024). However, the underlying factors driving metastasis and treatment resistance in ESCC are largely unknown.

Reticulocalbin 2 (RCN2), also called E6BP and ERC-55, is a calcium-binding protein localized in the endoplasmic reticulum (ER) lumen, and has six conserved regions that show high similarity to the EF-hand (a high-affinity Ca2 +-binding motif) (Weis et al., 1994). Studies have suggested that RCN2 overexpression is clinically correlated with recurrence and poor prognostic outcomes of patients with oral squamous cell carcinoma (OSCC) (Guo et al., 2025), hepatocellular carcinoma (HCC) (Mei et al., 2021), and colorectal cancer (CRC) (Wang et al., 2017). Moreover, RCN2 upregulation contributes to tumor progression of multiple cancer types such as OSCC (Guo et al., 2025), HCC (Mei et al., 2021), and CRC (Wang et al., 2017)) through activating distinct signaling pathways. For example, YY1 acts as a transcription factor of RCN2 to promote HCC progression by activating the MYC pathway (Mei et al., 2021). Furthermore, RCN2 promotes HCC proliferation by activating the EGFR-ERK pathway (Ding et al., 2017). Upregulated RCN2 activates the PKA-AKT-mTORC pathway to accelerate OSCC progression (Guo et al., 2025). RCN2 also activates the Wnt-β‑catenin pathway to facilitate proliferation, migration, and invasion of CRC cells (Wang et al., 2019a). In addition to activating multiple oncogenic signaling pathways, RCN2 also participates in inducing an immunosuppressive tumor microenvironment and impairs the efficacy of PD-L1-based immunochemotherapy in pancreatic cancer (Duan et al., 2023). Despite these findings, the biological function of RCN2 remains largely elusive. Besides, there are no reports on the role of RCN2 in ESCC.

Protein phosphatase 2 A (PP2A) is a family of serine-threonine phosphatases and has a key role in modulating protein phosphorylation against kinase activity (Haanen et al., 2022). PP2A is composed of a heteromeric core enzyme with a catalytic subunit and a constant regulatory subunit (Janssens and Goris, 2001). As a crucial component of PP2A, protein phosphatase 2 catalytic subunit alpha isoform (PPP2CA) participates in mediating cancer progression and is correlated with prognostic outcomes of cancer patients (Han et al., 2024, Yong et al., 2018, Zeng et al., 2022). Notably, PPP2CA negatively regulates mitogenic signaling pathways, thereby restraining tumor progression, metastasis, and drug resistance (Bakirtzi et al., 2011, Mao et al., 2024, Zeng et al., 2022). However, whether PPP2CA is involved in ESCC progression remains unexplored.

Ubiquitination is a highly conserved and fundamental posttranslational modification, which plays a crucial role in modulating protein stability (Liu et al., 2024a, Zhang et al., 2025). This posttranslational modification process is controlled by ubiquitin-activating (E1), -conjugating (E2), or -ligating (E3) enzymes. Ubiquitination plays a key role in PPP2CA protein degradation (Han et al., 2024). The E3 ubiquitin ligase GP78 promotes PPP2CA ubiquitination and degradation, thus enhancing DNA damage repair and contributing to breast cancer radioresistance (Han et al., 2024). Ubiquitin protein ligase E3 component N-recognin 5 (UBR5) is a HECT domain-containing ubiquitin ligase, which is frequently amplified and overexpressed in cancers (Chen et al., 2021, Song et al., 2024, Song et al., 2020). It has been found that UBR5 induces SOX2 ubiquitination and degradation to inhibit ESCC cell proliferation and stemness (Wang et al., 2019c). However, whether UBR5 affects ESCC metastasis and resistance remains unclear.

The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is one of the most important cellular processes and is abnormally activated in cancers (including ESCC), contributing to tumor proliferation, metastasis, and drug resistance (He et al., 2021, Luo et al., 2022). Numerous studies have demonstrated that many molecules regulate the PI3K-AKT pathway in ESCC (Liu et al., 2023, Wang et al., 2020, Xu et al., 2021). At present, several PI3K-AKT pathway inhibitors have been developed, which exert antitumor effects either alone or in combination with other inhibitors (Alzahrani, 2019). Identification of the upstream regulators of the PI3K-AKT pathway will enable us to gain a deeper understanding of its function.

The present study is the first to report that RCN2 upregulation is responsible for reinforcing ESCC progression, metastasis, and cisplatin resistance through modulating the RCN2-PPP2CA-PI3K-AKT axis. Mechanistically, RCN2 directly binds to PPP2CA and facilitates its degradation via the ubiquitin-proteasome system in a UBR5-dependent manner, with subsequent activation of the PI3K-AKT signaling pathway mainly through inducing AKT phosphorylation at Ser473 (p-AKT(S473). This study reveals the role of RCN2 as a novel prognostic biomarker and treatment target for ESCC.