BTN3A1 promotes tumor progression and radiation resistance in esophageal squamous cell carcinoma by regulating ULK1-mediated autophagy

Abstract

Radiotherapy is one of the most effective treatments for esophageal squamous cell carcinoma (ESCC); however, radioresistance is a clinical problem that must urgently be solved. Here, we found that butyrophilin subfamily 3 member A1 (BTN3A1) is upregulated in ESCC tumor tissues compared with nontumor tissues. We also evaluated BTN3A1 expression in patients with ESCC receiving adjuvant radiotherapy. The results demonstrated that BTN3A1 upregulation predicts a poor prognosis for ESCC patients. BTN3A1 overexpression promotes ESCC cell proliferation in vitro and in vivo. Moreover, BTN3A1 knockdown sensitized ESCC cells to radiation. We further explored the mode of death involved in BTN3A1-mediated radioresistance. Previous studies have shown that apoptosis, autophagy, necrosis, pyroptosis and ferroptosis are important for the survival of ESCC cells. We performed an RT-PCR array and western blotting (WB) to identify the mode of death and revealed for the first time that BTN3A1 promotes cell radioresistance by activating autophagy. In addition, by performing immunoprecipitation and mass spectrometry analyses, we found that BTN3A1 regulated the expression of UNC-51-like autophagy activating kinase 1(ULK1) and promoted its phosphorylation to subsequently initiate autophagy. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay results indicated that BTN3A1 is a novel direct target of hypoxia inducible factor-1α (HIF-1α). HIF-1α, a transcription factor, promotes BTN3A1 transcription upon irradiation. Overall, the present study is the first to show that BTN3A1 plays a key role in radioresistance and that targeting BTN3A1 might be a promising strategy to improve radiotherapy efficacy in patients with ESCC.

High expression of BTN3A1 is associated with clinical and immunological characteristics and predicts a poor prognosis in advanced human gliomas

“…The analysis of BTN3A1’s prognostic significance revealed an association between elevated BTN3A1 expression and poorer prognosis in glioma patients. Elevated BTN3A1 expression has also been linked to unfavorable outcomes in esophageal squamous cell carcinoma (ESCC), metastatic gastrointestinal stromal tumors (mGISTs), and ovarian cancer (OC) ( 27 , 32 , 65 ).…”

“…Additionally, the correlation of BTN3A expression with immune evasion strategies of pancreatic tumor (PC) cells reinforces the role of BTN3A in facilitating tumor progression ( 31 ). A notable recent study elucidated that BTN3A1 overexpression in esophageal squamous cell carcinoma (ESCC) augments radioresistance by modulating the expression and phosphorylation of UNC-51-like autophagy-activating kinase (ULK1), subsequently correlating with adverse prognoses ( 32 ).…”

SDC1-TGM2-FLOT1-BHMT complex determines radiosensitivity of glioblastoma by influencing the fusion of autophagosomes with lysosomes

“…Yamamoto et al indicated that autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 26 . Yang et al reported that BTN3A1 promotes tumor progression and radiation resistance in esophageal squamous cell carcinoma by regulating ULK1-mediated autophagy 27 . Wang et al also found that PLK1 inhibition enhances the radiosensitivity of breast cancer cells in a manner associated with the suppression of radiation-induced autophagy 28 .…”

Local γδ T cells: translating promise to practice in cancer immunotherapy

“…However, what is striking is their differential expression in steady-state epithelial tissues versus their respective neoplastic counterparts. This is most evident in BTN3A isoforms which are often upregulated in cancers relative to normal tissue counterparts [ 118 , 120 – 123 ] (Fig. 1 ).…”