No abstract

Background The Nuclear Factor kappaB (NF-kB) family consists of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. NF-kB has recently generated considerable interest as it has been implicated in human cancer initiation, progression and resistance to treatment. In the present comprehensive review the different aspects of NF-kB signaling in the carcinogenesis of cancer of the uterine cervix are discussed. NF-kB functions as part of a network, which determines the pattern of its effects on the expression of several other genes (such as crosstalks with reactive oxygen species, p53, STAT3 and miRNAS) and thus its function. Activation of NF-kB triggered by a HPV infection is playing an important role in the innate and adaptive immune response of the host. The virus induces down regulation of NF-kB to liquidate the inhibitory activity for its replication triggered by the immune system leading a status of persistant HPV infection. During the progression to high grade intraepithelial neoplasia and cervical cancer NF-KB becomes constitutionally activated again. Mutations in NF-kB genes are rare in solid tumors but mutations of upstream signaling molecules such as RAS, EGFR, PGF, HER2 have been implicated in elevated NF-kB signaling. NF-kB can stimulate transcription of proliferation regulating genes (eg. cyclin D1 and c-myc), genes involved in metastasis, VEGF dependent angiogenesis and cell immortality by telomerase. NF-kB activation can also induce the expression of activation-induced cytodine deaminase (AID) and the APOBEC proteins, providing a mechanistic link between the NF-kB pathway and mutagenic characteristic of cervical cancer. Inhibition of NF-kB has the potential to be used to reverse resistance to radiotherapy and systemic anti-cancer medication, but currently no clinicaly active NF-kB targeting strategies are available.

Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G 1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis.

Highlights Cancer patients with COVID-19 have a higher morbidity and mortality. Particularly patients with ongoing or recent cancer treatment, metastatic solid tumors and hematological malignancies are at risk. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status in cancer patients may fuel the effects of a SARS-CoV-2 sepsis. The gene expression level of ACE2 may be an indicator of the susceptibility to SARS-CoV-2 infection, while TMPRSS2 plays a supporting role. Better knowledge of the mechanisms involved may be a tool to identify high risk patients and to prevent severe complications by targeting the involved pathways.