An Oct-1-based, feed-forward mechanism of apoptosis inhibited by co-culture with Raji B-cells: Towards a model of the cancer cell/B-cell microenvironment

Abstract

A continuing conundrum of cancer biology is the dichotomous function of transcription factors that regulate both proliferation and apoptosis, seemingly opposite results. Previous results have indicated that regulated entry into the S-phase of the cell cycle can be anti-apoptotic. Indeed, tumor suppressor genes can be amplified in tumors and certain, slow growing cancers can represent a relatively poor prognosis, both phenomena likely related to reduced cancer cell apoptosis, in turn due to reduced, unproductive entry into S-phase. In this report, we demonstrate that the Oct-1 transcription factor, commonly considered pro-proliferative, indeed facilitates IFN-γ induced apoptosis in 5637 bladder carcinoma cells, consistent with the role of the retinoblastoma protein in down-regulating Oct-1 DNA binding activity and in suppressing IFN-γ induced apoptosis. More importantly, despite the commonly appreciated process of IFN-γ induced apoptosis, IFN-γ at low concentrations stimulated bladder cancer cell proliferation, consistent with apoptosis being dependent on an overstimulation of what is otherwise a pro-proliferative pathway. This observation is in turn consistent with a feed forward mechanism of apoptosis, whereby transcription factors activate proliferation-effector genes at relatively low levels, then apoptosis-effector genes when the transcription factors over-accumulate. Finally, Oct-1 mediated apoptosis is inhibited by co-culture with Raji B-cells, raising the question of whether the normal lymph node environment, or other microenvironments with high concentrations of B-cells, is protective against Oct-1 facilitated apoptosis?

An integrated analysis of cancer genes in thyroid cancer

“…POU class 2 homeobox 1 (POU2F1), also known as OCT1, is a ubiquitous member of the POU transcription factor family. POU2F1 shows pro-proliferative and pro-apoptotic activity in bladder carcinoma (41). Neurotrimin (NTM) and OPCML are members of the IgLON family of immunoglobulin (Ig) domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecules.…”

Identification of immunoglobulin V(D)J recombinations in solid tumor specimen exome files: Evidence for high level B-cell infiltrates in breast cancer

“…For example, it will be possible to determine whether B-cell infiltrates into the tumor micro-environment have an impact on prognosis, through minimization of apoptosis 4 or other tumorpromoting or tumor-destroying mechanisms; or whether there is an association of V and J usage with HLA types, as has been postulated for TcR V and J usage 9 ; or whether certain cancer mutations correlate with the detection of immunoglobulin recombinations or V and J usage. In addition, more recent studies have indicated that tumors with higher levels of mutations are more immunogenic, possibly due to a greater availability of neoantigens, based on T-cell responses.…”

“…3 We recently noted the negative impact of B-cells in an artificial micro-environment on tumor cell apoptosis. 4 To develop more precise methods of immunoscoring, potentially leading to more accurate methods of linking a B-cell related immunoscore to tumor outcome or to a specific therapy, we and others have developed genomics-based immunoscoring approaches. [5][6][7] Recently, the linkage of TcR and MHCII expression has been established for particular tumor specimens using RNASeq files, and TcR recombinations have been studied in tumor exome files.…”

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

“…10 Thus, while one CpG may not have a dramatic impact on expression levels as detected by routine laboratory approaches, the potential for a "shifting of the balance" remains important, particularly in considering such paradigms as feed-forward mechanisms of apoptosis, whereby a shift in transcription factor levels, as opposed to simple presence or absence of a transcription factor, likely determines the difference between cell proliferation and apoptosis. [11][12][13][14] It has become apparent that cancers traditionally representing different tissue types have extensive molecular overlaps, i.e., have many molecular bases in common for the cancer phenotype. 10,15 Thus, by taking a multi-cancer approach, it is possible to enhance statistical power when attempting to learn of potential over-representations of biomarkers in cancer.…”