Beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) is crucial for the degradation of IκBα. Our previous transcriptome sequencing analysis revealed that tetraspanin 15 (TSPAN15) was significantly upregulated in clinical oesophageal squamous cell carcinoma (OSCC) tissues. Here, we show that high TSPAN15 expression in OSCC tissues is significantly associated with lymph node and distant metastasis, advanced clinical stage, and poor prognosis. Elevated TSPAN15 expression is, in part, caused by the reduction of miR-339-5p. Functional studies demonstrate that TSPAN15 promotes metastatic capabilities of OSCC cells. We further show that TSPAN15 specifically interacts with BTRC to promote the ubiquitination and proteasomal degradation of p-IκBα, and thereby triggers NF-κB nuclear translocation and subsequent activation of transcription of several metastasis-related genes, including ICAM1, VCAM1, uPA, MMP9, TNFα, and CCL2. Collectively, our findings indicate that TSPAN15 may serve as a new biomarker and/or provide a novel therapeutic target to OSCC patients.

T-cell exhaustion was initially identified in chronic infection in mice and was subsequently described in humans with cancer. Although the distinct signature of exhausted T (TEX) cells in cancer has been well investigated, the molecular mechanism of T-cell exhaustion in cancer is not fully understood. Using single-cell RNA sequencing, we report here that TEX cells in esophageal cancer are more heterogeneous than previously clarified. Sprouty RTK signaling antagonist 1 (SPRY1) was notably enriched in two subsets of exhausted CD8+ T cells. When overexpressed, SPRY1 impaired T-cell activation by interacting with CBL, a negative regulator of ZAP-70 tyrosine phosphorylation. Data from the Tumor Immune Estimation Resource revealed a strong correlation between FGF2 and SPRY1 expression in esophageal cancer. High expression of FGF2 was evident in fibroblasts from esophageal cancer tissue and correlated with poor overall survival. In vitro administration of FGF2 significantly upregulated expression of SPRY1 in CD8+ T cells and attenuated T-cell receptor–triggered CD8+ T-cell activation. A mouse tumor model confirmed that overexpression of FGF2 in fibroblasts significantly upregulated SPRY1 expression in TEX cells, impaired T-cell cytotoxic activity, and promoted tumor growth. Thus, these findings identify FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells in esophageal cancer. Significance: These findings reveal FGF2 as an important regulator of SPRY1 expression involved in establishing the dysfunctional state of CD8+ T cells and suggest that inhibition of FGF2 has potential clinical value in ESCC.

Dormant cancer stem cells (DCSCs) exhibit characteristics of chemotherapy resistance and immune escape, and they are a crucial source of tumor recurrence and metastasis. However, the underlying mechanisms remain unrevealed. We demonstrate that enriched Gzmk ⁺ CD8 ⁺ T cells within the niche of esophageal DCSCs restrict the outgrowth of tumor mass. Nonetheless, DCSCs can escape immune elimination by enhancing PD-L1 signaling, thereby maintaining immune equilibrium. Quiescent fibroblast-derived quiescin sulfhydryl oxidase 1 (QSOX1) promotes the expression of PD-L1 and its own expression in DCSCs by elevating the level of reactive oxygen species. Additionally, high QSOX1 in the dormant tumor niche contributes to the exclusion of CD8 ⁺ T cells. Conversely, blocking QSOX1 with Ebselen in combination with anti-PD-1 and chemotherapy can effectively eradicate residual DCSCs by reducing PD-L1 expression and promoting CD8 ⁺ T cell infiltration. Clinically, high expression of QSOX1 predicts a poor response to anti-PD-1 treatment in patients with esophageal cancer. Thus, our findings reveal a mechanism whereby QSOX1 promotes PD-L1 upregulation and T cell exclusion, facilitating the immune escape of DCSCs, and QSOX1 inhibition, combined with immunotherapy and chemotherapy, represents a promising therapeutic approach for eliminating DCSCs and preventing recurrence.

Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks effective therapeutic targets. Here, we demonstrated that ectopic expression of trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed by foci formation in monolayer culture, colony formation in soft agar and orthotopic liver transplantation in nude mice. Inversely, silencing TROAP expression with short-hairpin RNA attenuated the malignant proliferation of HCC cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP directly bound to dual specificity tyrosine phosphorylation regulated kinase 1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a promising therapeutic target and prognostic indicator for patients with HCC.

Background: Ubiquitin specific peptidase 14 (USP14), a deubiquitinating enzyme, has been documented as a key element to regulate the proteolysis function of proteasomes and an attractive therapeutic target for several cancers. Herein, we elucidate the role of USP14 in predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC).Methods: USP14 expression was detected in ESCC tissues and matched adjacent non‐tumorous tissues by quantitative real‐time reverse transcription‐PCR and immunohistochemistry. Kaplan–Meier survival analysis was used to assess the correlation between USP14 expression and prognosis in ESCC patients. Univariate and multivariate analysis was conducted with a Cox proportional hazards model to determine whether USP14 is an independent prognostic factor.Result: Overexpression of USP14 was observed in approximately 60% of tested ESCC samples compared to their paired non‐tumor esophageal tissues at both RNA and protein levels, and was significantly associated with distant metastasis (P = 0.001). Kaplan–Meier analysis showed that USP14 overexpression was related to poorer overall patient survival. Univariate and multivariate analyses demonstrated that USP14 was an independent risk factor for overall survival.Conclusion: The findings in this study suggest that USP14 could be used as a potential prognostic marker for ESCC patients.