Introduction Bladder Cancer (BC) is the ninth most common cancer worldwide. Non-Muscle Invasive Bladder Cancer (NMIBC) is a heterogeneous disease that includes tumours with low and high risk of progression to muscle invasion. Nowadays, clinico-pathological features alone are not sufficient to effectively classify these patients and the discovery of new biomarkers is essential to increase quality of their life, who should only be treated with a radical high-morbidity approach, whenever needed, depending on the type of NMIBC tumour developed. ▵Np63 has previously been reported by our group as a protective factor of High Grade (HG) NMIBC progression: From the patients whose tumours showed nuclear ▵Np63 expression, none suffered disease progression after a median follow-up of 62,1 months. Furthermore, when ▵Np63 was knocked down (ΔNKO), cells showed higher proliferation and invasive capacities in vitro and higher tumour and metastasis formation in vivo. Interestingly, ΔNKO cells displayed AGR2 gene up-regulation and protein overexpression. Material and methods Two commercially available HG-NMIBC cell lines (RT112 and BF-TC905) were used to study the role of AGR2 in tumour progression. A stable knockdown of AGR2 (using shRNA technology) was performed on ΔNKO cells. In vitro functional studies, such as cell cycle, proliferation and invasion assays were performed comparing parental cells, ΔNKO cells and cells with knockdown of both ▵Np63 and AGR2 (AKO). The orthotopic mouse model is being used to study in vivotumour initiation and metastatic capacities. Immunofluorescence analyses of AGR2 in human HG-NMIBC tissue specimens will be performed to see if AGR2 expression is a prognostic and predictive biomarker for HG-NMIBC. Results and discussions After knocking down AGR2 in RT112 and BF-TC905 ▵NKO cells, we observed a reversal of the aggressive phenotype of ΔNKO cells, with lower cell proliferation (cell cycle analysis and proliferation assay) and invasion, thus confirming the functional importance of AGR2. If in vivo results corroborate our hypothesis, we will start a collaboration with Dr. Li’s lab to test the efficiency of AGR2 antibody (Agtuzumab) intravesical therapy in NMIBC. Conclusion This work uncovered AGR2 as a progression biomarker in HG-NMIBC, allowing a better understanding of the mechanisms of BC progression, and opening the possibility of novel therapies for patients affected by this disease, ultimately improving patients overall survival and quality of life.