USO1 expression is dysregulated in non-small cell lung cancer

Anna Keogh; Lisa Ryan; Mutaz M Nur; Anne-Marie Baird; Siobhan Nicholson; Sinéad Cuffe; Gerard J Fitzmaurice; Ronan Ryan; Vincent K Young; Stephen P Finn; Steven G Gray

doi:10.21037/tlcr-22-230

USO1 expression is dysregulated in non-small cell lung cancer

Transl Lung Cancer Res. 2022 Sep;11(9):1877-1895. doi: 10.21037/tlcr-22-230.

Authors

Anna Keogh^{1

2}, Lisa Ryan³, Mutaz M Nur^{1

4}, Anne-Marie Baird^{1

2}, Siobhan Nicholson³, Sinéad Cuffe⁵, Gerard J Fitzmaurice⁶, Ronan Ryan⁶, Vincent K Young⁶, Stephen P Finn^{1

2

7

8}, Steven G Gray^{1

2

9

10}

Affiliations

¹ Thoracic Oncology Research Group, Laboratory Medicine and Molecular Pathology, Central Pathology Laboratory, St. James's Hospital, Dublin, Ireland.
² School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
³ Department of Histopathology, Labmed Directorate, St. James's Hospital, Dublin, Ireland.
⁴ Division of Pathology, Department of Medicine, University Hospital Waterford, Waterford, Ireland.
⁵ HOPE Directorate, St James's Hospital, Dublin, Ireland.
⁶ Surgery, Anaesthesia and Critical Care Directorate, St James's Hospital, Dublin, Ireland.
⁷ Cancer Molecular Diagnostics, Labmed Directorate, St. James's Hospital, Dublin, Ireland.
⁸ Department of Histopathology and Morbid Anatomy, Trinity College Dublin, Dublin, Ireland.
⁹ Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
¹⁰ School of Biological Sciences, Technological University Dublin, Dublin, Ireland.

Abstract

Background: USO1 vesicle transport factor (USO1) is a vesicular transport factor crucial for endoplasmic reticulum (ER) to Golgi transport and is required for transcytotic fusion and subsequent binding of the vesicles to the target membrane. USO1 has been studied in multiple cancers revealing high levels of expression and exerting its oncogenic role by increasing cell proliferation and evasion of apoptosis. Furthermore, multiple studies have implicated dysregulation of the Erk signalling pathway in the involvement of USO1 in multiple cancers. Overall survival (OS) in non-small cell lung cancer (NSCLC) remains low despite recent advances in treatments which are mainly due to the late stage of diagnosis and a significant cohort of patients lacking an available targeted therapy. The aim of this study was to investigate USO1 expression in NSCLC.

Methods: An in-house NSCLC tissue microarray (TMA) comprising (n=204 patients) was stained for USO1. Scoring intensity (H score) was used to interrogate for correlations between USO1 expression and established prognostic factors, and OS. Further evaluation of the expression of USO1 in NSCLC was done using multiple online datasets including Lung Cancer Explorer (LCE), UALCAN, GEPIA, KM plotter, TIMER2 and MuTarget.

Results: USO1, when highly expressed in lung adenocarcinomas (LUADs) leads to a significantly increased OS (P=0.028). There was no significant correlation between age, smoking status, lymph node status, tumour subgroup and stage. USO1 was significantly higher in patients with tumour size <5 cm compared to those ≥5 cm (P=0.016). Overexpression in LUAD occurred at an early stage being significantly upregulated in Stage 1 and N0 tumours. USO1's first neighbours, also involved in ER-Golgi transport have altered expression in LUAD and significantly impact overall survival. Overexpression occurred independently of commonly mutated genes in NSCLC and had no correlation with changes in the TME.

Conclusions: This study highlights the importance of USO1 and ER-Golgi vesicular transport system in LUAD. USO1 overexpression occurs as an early event in LUAD and independently of commonly mutated genes in NSCLC and therefore may represent an attractive diagnostic biomarker as well as a potential target for treatment.

Keywords: USO1; non-small cell lung cancer (NSCLC); overall survival (OS).