Ribonuclease T2 (RNASET2) expression in the spectrum of neuroendocrine neoplasms of the lung. Relationships with hypoxia-related mechanisms and microvascular patterns

Background & Objective: RNASET2 exerts several different activities in neoplastic cells since the early steps of tumour development such as growth suppression and antiangiogenic activity. No data on its expression in neuroendocrine neoplasms of the lung (Lu-NENs) are available. We investigated RNASET2 expression in well-differentiated (WD) and poorly differentiated (PD) Lu-NENs. In addition, we explored possible relationships between RNASET2 expression and a series of immunohistochemical markers related to hypoxic stress, apoptosis, proliferation and angiogenesis. Method: Twenty-nine surgically resected Lu-NENs diagnosed between 2007 and 2016 were analyzed and compared to normal lung tissues from six lobectomies. Immunohistochemical stains for RNASET2, HIF-1 alpha, CAIX, M30, synaptophysin, chromogranin A, CD31 and CD34 were evaluated. RNASET2 expression was also measured with quantitative RT Real Time PCR. HIF-1 alpha expression in transfected cells was evaluated 48h after transfection by western blot analysis. Results: Our results showed a significantly higher expression of RNASET2, HIF-1 alpha, and CAIX in PD Lu-NENs, associated with a higher proliferation and apoptotic rates, as well as a lower microvessel density (MVD) compared to WD Lu-NENs. In vitro, we demonstrated an overexpression of RNASET2 consequent to the activation of HIF-1 alpha. Conclusion: We suggest that in PD Lu-NENs, RNASET2 expression may be induced by HIF-1 alpha. In this aggressive group of cancers, RNASET2 fails to exert the growth-inhibiting effects described in other types of neoplasms. However, it may contribute to the typical phenotypic alterations seen in poorly differentiated Lu-NENs, such as low MVD, high apoptotic rate and extensive necrosis.