Evaluation of cationic channel TRPV2 as a novel biomarker and therapeutic target in Leukemia-Implications concerning the resolution of pulmonary inflammation

Abstract

Patients treated during leukemia face the risk of complications including pulmonary dysfunction that may result from infiltration of leukemic blast cells (LBCs) into lung parenchyma and interstitium. In LBCs, we demonstrated that transient receptor potential vanilloid type 2 channel (TRPV2), reputed for its role in inflammatory processes, exhibited oncogenic activity associated with alteration of its molecular expression profile. TRPV2 was overexpressed in LBCs compared to normal human peripheral blood mononuclear cells (PBMCs). Additionally, functional full length isoform and nonfunctional short form pore-less variant of TRPV2 protein were up-regulated and down-regulated respectively in LBCs. However, the opposite was found in PBMCs. TRPV2 silencing or pharmacological targeting by Tranilast (TL) or SKF96365 (SKF) triggered caspace-mediated apoptosis and cell cycle arrest. TL and SKF inhibited chemotactic peptide fMLP-induced response linked to TRPV2 Ca2+ activity, and down-regulated expression of surface marker CD38 involved in leukemia and lung airway inflammation. Challenging lung airway epithelial cells (AECs) with LBCs decreased (by more than 50%) transepithelial resistance (TER) denoting barrier function alteration. Importantly, TL prevented such loss in TER. Therefore, TRPV2 merits further exploration as a pharmacodynamic biomarker for leukemia patients (with pulmonary inflammation) who might be suitable for a novel [adjuvant] therapeutic strategy based on TL.

Construction of prognostic predictor by comprehensive analyzing alternative splicing events for colon adenocarcinoma

“…Abnormal AS has been identified as a molecular trigger for cancer [ 14 ]. Various studies have shown that the transcript variants of a gene may have opposing roles, and AS is known to be a key factor in cancer progression, including proliferation, apoptosis, invasion, angiogenesis, and metabolism [ 15 , 16 ]. For example, an EGFR splice variant, lacks exon 4 (de4 EGFR), was found to constitutively activate downstream pathways to promote cancer cell proliferation and metastasis in glioma, prostate cancer, and ovarian cancer tissues [ 17 ].…”

Construction of prognostic predictor by comprehensive analyzing alternative splicing events for Colon adenocarcinoma

“…Abnormal AS has been identi ed as a molecular trigger for cancer [14]. Various studies have shown that the transcript variants of a gene may have opposing roles, and AS is known to be a key factor in cancer progression, including proliferation, apoptosis, invasion, angiogenesis, and metabolism [15,16]. For example, an EGFR splice variant, lacksexon 4 (de4 EGFR), was found to constitutively activate downstream pathways to promote cancer cell proliferation and metastasis in glioma, prostate cancer, and ovarian cancer tissues [17].…”

Transient Receptor Potential (TRP) Channels in Haematological Malignancies: An Update

“…Its expressions are higher (about sixfold) in leukaemia cells than in peripheral blood mononuclear cells (PBMCs). Interestingly, the THP-1 and U937 cells express two different TRPV2 isoforms: the full-length glycosylated form (f-TRPV2), and the short form (s-TRPV2), which exerts an inhibitory activity blocking the translocation of the full one [45]. The THP-1 cells express a lower amount of f-TRPV2 and higher levels of s-TRPV2 with respect to U937.…”

“…This result suggests that inhibition of f-TRPV2 expression determines a reduction in its oncogenic activity. Moreover, it has been demonstrated that SFK induces p38 activation, decreases the expression of Bcl-2 and ERK 1 and 2, and increases the inactivated form of the poly(ADP-ribose) polymerase (PARP) and cleaved caspase-3 [45].…”