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See detailInsight into the mechanisms underlying the oncogenic potential of BCL-3 through transcriptomic studies
Zhang, Xin ULg

Doctoral thesis (2013)

Constitutive NF-κB activation, a hallmark of many hematological and solid tumors, disrupts the balance between apoptosis and proliferation by upregulating the expression of anti-apoptotic genes, thus ... [more ▼]

Constitutive NF-κB activation, a hallmark of many hematological and solid tumors, disrupts the balance between apoptosis and proliferation by upregulating the expression of anti-apoptotic genes, thus promoting cell growth and controlling angiogenesis, invasion and metastasis. Studies that addressed the roles of NF-κB in normal epidermis and in skin cancers led to conflicting results. Indeed, while enhanced NF-κB activities were reported in squamous cell carcinomas, inhibition of this pathway in normal epidermis paradoxically promoted cell carcinoma. Similarly, despite a constitutive NF-κB activity seen in cervical cancer, the precise role of NF-κB in the development of these tumours, which are associated with human papillomavirus (HPV) infection, also remains unclear. We define here PINB (for Protein induced by NF-kappaB and BCL-3) as a BCL-3- and p65-dependent gene in transformed keratinocytes. PINB expression is enhanced upon human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, PINB binds Plexin A2, stabilizes EGFR and links Semaphorin 3A signalling cascades to EGFR phosphorylation. Moreover, PINB protects from Semaphorin 3A-mediated cell death and promotes EGF-mediated epithelial-mesenchymal transition (EMT) through the Ras/MEK1/ERK1/2 pathway. Taken together, our data define PINB as an oncogenic protein induced by constitutive NF-kappaB activity that transmits prosurvival and invasive signals through EGFR. In conclusion, we revealed new mechanisms by which constitutive NF-κB activation is linked to keratinocyte transformation in the skin and cervix. [less ▲]

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