A study of Alternative TrkA Splicing identifies TrkAIII as a novel potentially targetable participant in PitNET progression.Type of the Paper (Article)

Sbaffone, M.; Jaffrain-Rea, M.-L.; Cappabianca, L.; Carbonara, F.; Gianno, F.; Feola, T.; Ruggieri, M.; Zelli, V.; Maccarone, R.; Guadagni, S.; Clementi, M.; Arcella, A.; Esposito, V.; Carozza, G.; Martelli, I.; Farina, A.R.; Mackay, A.R. A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression. Biology 2024, 13, 171. Sbaffone, M.; Jaffrain-Rea, M.-L.; Cappabianca, L.; Carbonara, F.; Gianno, F.; Feola, T.; Ruggieri, M.; Zelli, V.; Maccarone, R.; Guadagni, S.; Clementi, M.; Arcella, A.; Esposito, V.; Carozza, G.; Martelli, I.; Farina, A.R.; Mackay, A.R. A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression. Biology 2024, 13, 171.

Abstract

PitNETs, although typically benign, comprise a small percentage of therapy-resistant aggressive, occasionally metastatic tumors, underpinning a need to identify novel therapeutic targets. PitNETs carry few mutations but associate with conditions that promote alternative splicing as an oncogenic alternative and express the TrkA neurotrophin receptor, which exhibits oncogenic alternative TrkAIII splicing in other tumors. Alternative TrkAIII splicing was assessed by RT-PCR in 53 PitNETs and compared to HIF1a, HIF2a, SF3B1, SRSF2, U2AF1 and JCPyV large T antigen mRNA expression, unconventional Xbp1 splicing, SF3B1 mutation, and TrkA isoform(s) immunoreactivity by confocal immunofluorescence (IF). Alternative TrkAIII mRNA splicing was detected in all invasive PitNET phenotypes, was significantly elevated in invasive compared to non-invasive PIT1 PitNETs, relatively high in invasive and non-invasive SF1 and TPIT PitNETs, and was associated with IF consistent with intracellular TrkAIII activation but not with hotspot SF3B1 mutations, altered SF3B1, SRSF2 and U2AF1 splice factor mRNA expression, JCPyV large T antigen expression or unconventional Xbp1 splicing. A potential role for hypoxia in TrkAIII mRNA splicing was supported by significant elevation of HIF2a mRNA expression in invasive PIT1 PitNETs. These data demonstrate that alternative TrkAIII splicing, potentially promoted by hypoxia, occurs frequently in PitNETs and may associate with IF consistent with intracellular TrkAIII activation, supporting a potential role for TrkAIII in PitNET pathogenesis and progression, identifying TrkAIII as a novel potential target in refractory PitNETs.

Keywords

PitNETs; alternative splicing, TrkAIII splice variant; HIF2a, Splice factors SF3B1, U2AF and SRSF2, hotspot SF3B1 mutation, Xbp1, JCPyV large T antigen

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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