The c-Jun and JunB transcription factors facilitate the transit of classical Hodgkin lymphoma tumour cells through G1

Abstract

Classical Hodgkin Lymphoma (cHL) is primarily a B cell lymphoid neoplasm and a member of the CD30–positive lymphomas. cHL and the other CD30–positive lymphomas are characterized by the elevated expression and/or constitutive activation of the activator protein-1 (AP-1) family transcription factors, c-Jun and JunB; however, the specific roles they play in the pathobiology of cHL are unclear. In this report we show that reducing either c-Jun or JunB expression with short-hairpin RNAs (shRNAs) reduced the growth of cHL cell lines in vitro and in vivo, primarily through impairing cell cycle transition through G1. We further investigated the effect of c-Jun and JunB knock-down on proliferation in another CD30–positive lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL). We found that JunB knock-down in most ALK+ ALCL cell lines examined also resulted in reduced proliferation that was associated with a G0/G1 cell cycle defect. In contrast, c-Jun knock-down in multiple ALK+ ALCL cell lines had no effect on proliferation. In summary, this study directly establishes that both c-Jun and JunB play roles in promoting HRS cell proliferation. Furthermore, we demonstrate there are similarities and differences in c-Jun and JunB function between cHL and ALK+ ALCL.

<p>Inhibition of ERKs/Akt-Mediated c-Fos Expression Is Required for Piperlongumine-Induced Cyclin D1 Downregulation and Tumor Suppression in Colorectal Cancer Cells</p>

“…37,38 Deregulation of AP-1 activity is implicated in the tumorigenesis of both solid tumors and lymphomas. 39,40 Importantly, the proto-oncogene c-Fos is the human homolog of the retroviral oncogene v-fos, which is linked to cancer due to the in vitro neoplastic transformation of normal cells. Overexpression of c-Fos promotes proliferation, angiogenesis, and survival of cancer cells.…”

AP-1 family transcription factors: a diverse family of proteins that regulate varied cellular activities in classical hodgkin lymphoma and ALK+ ALCL

“…A role for specific AP-1 proteins in the regulation of proliferation has been revealed by short interfering RNA (siRNA)/short hairpin RNA (shRNA) knock-down and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knock-out studies. Several groups have reported that JunB knock-down, in most ALK+ ALCL cell lines, decreased proliferation [ 89 – 91 ]. The common cell cycle defect observed in these studies was an increased percentage of cells in G 0 /G 1 with decreased percentages of cells in G 2 /M [ 89 ] or S [ 90 , 91 ] phase.…”

“…Several groups have reported that JunB knock-down, in most ALK+ ALCL cell lines, decreased proliferation [ 89 – 91 ]. The common cell cycle defect observed in these studies was an increased percentage of cells in G 0 /G 1 with decreased percentages of cells in G 2 /M [ 89 ] or S [ 90 , 91 ] phase. These defects correlated with decreased expression of CDK2 and multiple cyclins including Cyclin A2, Cyclin D2, Cyclin D3, and Cyclin E, as well as increased expression of CDK inhibitors p14 ink4A , p18 ink4 , p21 cip1 and p27 kip1 [ 90 , 91 ].…”

“…In cHL, stable knock-down of either c-Jun or JunB with shRNA was shown to reduce proliferation. This was characterized by an increased percentage of cells in G 0 /G 1 and a decreased percentage in S phase, and likely due to elevated p21 cip1 levels [ 91 ].…”

“…Knock-down of all AP-1 proteins is not associated with apoptosis in these lymphomas. Stable knock-down of c-Jun or JunB in multiple cHL and ALK+ ALCL cell lines was not associated with significant apoptosis as measured by TUNEL staining [ 91 ]. However, loss of both c-Jun and JunB was associated with increased apoptosis in the CD4-NPM-ALK model as was inhibition of PDGFRβ activity with Imatinib [ 93 ].…”