CD10 inhibits cell motility but expression is associated with advanced stage disease in colorectal cancer.

INTRODUCTION: CD10 is a cell membrane-bound endopeptidase which is expressed in normal small bowel but not in normal colon. It is aberrantly expressed in a small proportion of colorectal cancers (CRC) and this has been associated with liver metastasis and poor prognosis. We sought to investigate the mechanism of CD10 activity and its association with clinicopathological features. MATERIAL AND METHODS: CD10 was stably knocked down by lentiviral shRNA transduction in the CRC cell lines SW480 and SW620 which are derived from a primary tumour and its corresponding metastasis respectively. Expression of epithelial - mesenchymal transition (EMT) markers was tested as well as the effect of knockdown on cell viability, migration and invasion assays. In addition, immunohistochemical expression of CD10 in primary colorectal tumours (N = 84) in a tissue microarray was digitally quantified and analysed for associations with clinicopathological variables. RESULTS: Knockdown of CD10 did not alter cell viability in SW480, but migration and invasion levels increased (P < 0.001 for each) and this was associated with a cadherin switch. In SW620, CD10 knockdown caused a reduction in cell viability after 72 h (P = 0.0018) but it had no effect on cell migration and invasion. Expression of epithelial CD10 in primary tumours was associated with presence of lymph node invasion (P = 0.001) and advanced Duke's stage (P = 0.001). CONCLUSIONS: Our results suggest that the function of CD10 may change during tumour evolution. It may inhibit cell motility in early-stage disease whilst promoting cell viability in late-stage disease. It has a complex role and further studies are needed to elucidate the suitability of CD10 as a prognostic marker or therapeutic target.

Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma.

Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. SIGNIFICANCE: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.

Correction to: Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines.

An amendment to this paper has been published and can be accessed via the original article.

Characterising a human endogenous retrovirus(HERV)-derived tumour-associated antigen: enriched RNA-Seq analysis of HERV-K(HML-2) in mantle cell lymphoma cell lines.

BACKGROUND: The cell-surface attachment protein (Env) of the HERV-K(HML-2) lineage of endogenous retroviruses is a potentially attractive tumour-associated antigen for anti-cancer immunotherapy. The human genome contains around 100 integrated copies (called proviruses or loci) of the HERV-K(HML-2) virus and we argue that it is important for therapy development to know which and how many of these contribute to protein expression, and how this varies across tissues. We measured relative provirus expression in HERV-K(HML-2), using enriched RNA-Seq analysis with both short- and long-read sequencing, in three Mantle Cell Lymphoma cell lines (JVM2, Granta519 and REC1). We also confirmed expression of the Env protein in two of our cell lines using Western blotting, and analysed provirus expression data from all other relevant published studies. RESULTS: Firstly, in both our and other reanalysed studies, approximately 10% of the transcripts mapping to HERV-K(HML-2) came from Env-encoding proviruses. Secondly, in one cell line the majority of the protein expression appears to come from one provirus (12q14.1). Thirdly, we find a strong tissue-specific pattern of provirus expression. CONCLUSIONS: A possible dependency of Env expression on a single provirus, combined with the earlier observation that this provirus is not present in all individuals and a general pattern of tissue-specific expression among proviruses, has serious implications for future HERV-K(HML-2)-targeted immunotherapy. Further research into HERV-K(HML-2) as a possible tumour-associated antigen in blood cancers requires a more targeted, proteome-based, screening protocol that will consider these polymorphisms within HERV-K(HML-2). We include a plan (and necessary alignments) for such work.