BackgroundDiminished expression or activity of prostate apoptosis response protein 4 (Par-4) has been demonstrated in a number of cancers, although reports on Par-4 expression during colon cancer progression are lacking. An understanding of the molecular events in conjunction with the genetic networks affected by Par-4 is warranted.ResultsColon cancer specimens derived from patients have significantly diminished expression of Par-4 mRNA relative to paired normal colon. Hence, the functional consequences of reintroducing Par-4 into HT29 colon cancer cells were assessed. Overexpression augmented the interaction of Par-4 with NFκB in the cytosol but not nucleus, and facilitated apoptosis in the presence of 5-fluorouracil (5-FU). Analogous findings were obtained when AKT1 pro-survival signaling was inhibited. Transcriptome profiling identified ~700 genes differentially regulated by Par-4 overexpression in HT29 cells. Nearly all Par-4-regulated genes were shown by promoter analysis to contain cis-binding sequences for NFκB, and meta-analysis of patient expression data revealed that one-third of these genes exist as a recurrent co-regulated network in colon cancer specimens. Sets of genes involved in programmed cell death, cell cycle regulation and interestingly the microRNA pathway were found overrepresented in the network. Noteworthy, Par-4 overexpression decreased NFκB occupancy at the promoter of one particular network gene DROSHA, encoding a microRNA processing enzyme. The resulting down-regulation of DROSHA was associated with expression changes in a cohort of microRNAs. Many of these microRNAs are predicted to target mRNAs encoding proteins with apoptosis-related functions. Western and functional analyses were employed to validate several predictions. For instance, miR-34a up-regulation corresponded with a down-regulation of BCL2 protein. Treating Par-4-overexpressing HT29 cells with a miR-34a antagomir functionally reversed both BCL2 down-regulation and apoptosis by 5-FU. Conversely, bypassing Par-4 overexpression by direct knockdown of DROSHA expression in native HT29 cells increased miR-34a expression and 5-FU sensitivity.ConclusionOur findings suggest that the initiation of apoptotic sensitivity in colon cancer cells can be mediated by Par-4 binding to NFκB in the cytoplasm with consequential changes in the expression of microRNA pathway components.

Purpose of Review Patients with Lynch syndrome have a high probability of developing colorectal and other carcinomas. This review provides a comprehensive assessment of the immunologic aspects of Lynch syndrome pathogenesis and provides an overview of potential immune interventions for patients with Lynch syndrome polyps and Lynch syndrome–associated carcinomas. Recent Findings Immunogenic properties of the majority of Lynch syndrome polyps and associated cancers include microsatellite instability leading to a high mutational burden and the development of novel frameshift peptides, i.e., neoantigens. In addition, patients with Lynch syndrome develop T cell responses in the periphery and in the tumor microenvironment (TME) to tumor-associated antigens, and a proinflammatory cytokine TME has also been identified. However, Lynch syndrome lesions also possess immunosuppressive entities such as alterations in MHC class I antigen presentation, TGFβ receptor mutations, regulatory T cells, and upregulation of PD-L1 on tumor-associated lymphocytes. Summary The rich immune microenvironment of Lynch syndrome polyps and associated carcinomas provides an opportunity to employ the spectrum of immune-mediating agents now available to induce and enhance host immune responses and/or to also reduce immunosuppressive entities. These agents can be employed in the so-called prevention trials for the treatment of patients with Lynch syndrome polyps and for trials in patients with Lynch syndrome–associated cancers.

Nkx2-3 may contribute to the pathogenesis of IBD-associated CRC and sporadic CRC by regulating the Wnt signaling pathway.