Gene Expression Levels of the Prolyl Hydroxylase Domain Proteins <i>PHD1</i> and <i>PHD2</i> but Not <i>PHD3</i> Are Decreased in Primary Tumours and Correlate with Poor Prognosis of Patients with Surgically Resected Non-Small-Cell Lung Cancer

• Main Authors: Ana Koren, Matija Rijavec, Tomaž Krumpestar, Izidor Kern, Aleksander Sadikov, Tanja Čufer, Peter Korošec
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Cancers
• Subjects: non-small-cell lung cancer; prolyl hydroxylase domain proteins; mRNA expression; prognosis
• Online Access: https://www.mdpi.com/2072-6694/13/10/2309

Background: Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) play a role in cell oxygen sensing, negatively regulating the hypoxia-inducible factor (HIF) pathway. Our study aim was to evaluate <i>PHD1</i>, <i>PHD2</i> and <i>PHD3</i> mRNA expression levels in primary tumours and normal lungs of non-small-cell lung cancer (NSCLC) patients and to correlate it with selected regulators of HIF signalling, with clinicopathological characteristics and overall survival (OS). Methods: Tumour tissue samples were obtained from 60 patients with surgically resected NSCLC who were treated with radical surgery. In 22 out of 60 cases, matching morphologically normal lung tissue was obtained. <i>PHD1</i>, <i>PHD2</i> and <i>PHD3</i> mRNA expressions were measured using RT-qPCR. Results: The <i>PHD1</i> and <i>PHD2</i> mRNA levels in primary tumours were significantly decreased compared to those in normal lungs (both <i>p</i> < 0.0001). <i>PHD1</i> and <i>PHD2</i> expression in tumours was positively correlated (<i>r_s</i> = 0.82; <i>p</i> < 0.0001) and correlated well with HIF pathway downstream genes <i>HIF1A</i>, <i>PKM2</i> and <i>PDK1</i>. Decreased <i>PHD1</i> and <i>PHD2</i> were associated with larger tumour size, higher tumour stage (<i>PHD1</i> only) and squamous cell carcinoma. Patients with low <i>PHD1</i> and patients with low <i>PHD2</i> expression had shorter OS than patients with high <i>PHD1</i> (<i>p</i> = 0.02) and <i>PHD2</i> expression (<i>p</i> = 0.01). <i>PHD1</i> showed borderline independent prognostic values in multivariate analysis (<i>p</i> = 0.06). In contrast, we found no associations between <i>PHD3</i> expression and any of the observed parameters. Conclusions: Our results show that reduced expression of <i>PHD1</i> and <i>PHD2</i> is associated with the development and progression of NSCLC. <i>PHD1</i> could be further assessed as a prognostic marker in NSCLC.