Abstract
Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is identified as a novel cell surface marker for human T-cell leukemia virus (HTLV-1)-infected T cells. Adult T-cell leukemia/lymphoma (ATLL) is developed in HTLV-1-infected T-cells after a long infection period. To examine the mechanism of CADM1 overexpression in ATLL, we first identified that CADM1 is transcriptionally up-regulated by a transcriptional enhancer element through NF-κB signaling pathway. In HTLV-1-infected T-cells, CADM1 expression is dependent on HTLV-1/Tax through activation of canonical and non-canonical NF-κB; however, in ATLL cells with frequent loss of Tax expression, the activation of canonical NF-κB only enhances the CADM1 expression. Along with active mutations in signaling molecules under T-cell recepor (TCR) signaling, degradation of p47, a negative regulator of NF-κB, was essential for activation of canonical NF-κB through stabilization of NEMO (NF-κB essential modulator). The mechanism of p47 degradation is primarily dependent on activation of lysosomal-autophagy and the autophagy is activated in most of the HTLV-infected and ATLL cells, suggesting that the p47 degradation may be a first key molecular event during HTLV-1 infection to T-cells as a connector of two important signaling pathways, NF-κB and autophagy.
Highlights
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of CD4+ T-cells associated with human T-cell leukemia virus type 1 (HTLV-1) infection
We found that peripheral blood lymphocytes immortalized by Tax expressed Cell adhesion molecule 1 (CADM1), which was comparable to the levels in Adult T-cell leukemia/ lymphoma (ATLL)-derived cell lines (Fig. 1C), indicating that CADM1 is overexpressed in both Tax-positive HTLV-1-infected T-cells and Taxnegative ATLL cells
Semiquantitative Reverse transcription (RT)-polymerase chain reaction (PCR) analysis for CADM1, Tax, LC3B, A20, CYLD, p47 and NEMO was performed in two T-cell acute lymphoblastic leukemia (T-ALL) cell lines (Jurkat and MOLT4), three HTLV-1-infected T-cell lines (HUT102, MT2, and MT4), and three ATLL cell lines (S1T, KOB, and KK1). β-actin was used as a loading control. (B) Immunoblot analysis of CADM1, Tax, and the indicated nuclear factor-κB (NF-κB) and autophagy signaling proteins was performed in the same series of cell lines used in Fig. 4A. β-actin was used as a loading control
Summary
Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of CD4+ T-cells associated with human T-cell leukemia virus type 1 (HTLV-1) infection. The CADM1 gene was originally identified as a tumor suppressor gene in non-small cell lung cancer, and the loss of CADM1 expression is associated with a poor prognosis and metastasis in various types of solid cancers[2]. In HTLV-1-infected T-cells, Tax was reported to activate the canonical and noncanonical NF-κB signaling pathways through the association with various signaling proteins, including IκB kinase (IKK) and NF-κB transcriptional complex[10]. Activation of the NF-κB pathway is observed in ATLL cells with low levels of Tax expression through mechanisms involving the down-regulation of miR-31 and frequent somatic alterations in the TCR-NF-κB pathway[11,12]. Because the NF-κB pathway plays important roles in the survival and proliferation of HTLV-1-infected T-cells and ATLL cells, there must be some additional mechanism to ensure the sustained activation of the NF-κB pathway in ATLL cells
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