Cyclin D1 promotes cell cycle progression during G1 phase, a key event in G1-S transition. The protein is encoded by gene CCND1, located in chromosomal band 11q13. Cyclin D1 plays key roles in cell biology, including cell proliferation and growth regulation, mitochondrial activity modulation, DNA repair, and cell migration control. CCND1 gene and its protein cyclin D1 are frequently altered by different molecular mechanisms, including amplification, chromosomal translocations, mutations, and activation of the pathways involved in cyclin D1 expression, alterations which appear to be essential in the development of human cancers, including oral carcinoma. This is the first published review of the specific features of cyclin D1 overexpression in oral oncogenesis. Starting with the physiological regulation of cyclin D1, there is an evaluation of its functions, overexpression mechanisms, and the implications of the oncogenic activation of CCND1/cyclin D1 in oral squamous cell carcinoma. The potential diagnostic and prognostic value of cyclin D1 is reviewed. The influence of CCND1/cyclin D1 on tumor size and clinical stage is reported, and an update is provided on the utilization of cyclin D1 as therapeutic target and on the combination of cyclin D1 inhibitors with cytotoxic agents. Future research lines in this field are also proposed.

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Cortactin is a protein encoded by the CTTN gene, localized on chromosome band 11q13. As a result of the amplification of this band, an important event in oral carcinogenesis, CTTN is also usually amplified, promoting the frequent overexpression of cortactin. Cortactin enhances cell migration in oral cancer, playing a key role in the regulation of filamentous actin and of protrusive structures (invadopodia and lamellipodia) on the cell membrane that are necessary for the acquisition of a migratory phenotype. We also analyze a series of emerging functions that cortactin may exert in oral cancer (cell proliferation, angiogenesis, regulation of exosomes, and interactions with the tumor microenvironment). We review its molecular structure, its most important interactions (with Src, Arp2/3 complex, and SH3-binding partners), the regulation of its functions, and its specific oncogenic role in oral cancer. We explore the mechanisms of its overexpression in cancer, mainly related to genetic amplification. We analyze the prognostic implications of the oncogenic activation of cortactin in potentially malignant disorders and in head and neck cancer, where it appears to be relevant in the development of lymph node metastasis. Finally, we discuss its usefulness as a therapeutic target and suggest future research lines.

Paradoxical reactions during treatment with biological agents may be defined as an appearance or exacerbation of a pathological condition that usually responds to this class of drug. Typical examples of paradoxical adverse effect are, among others, palmoplantar pustular and psoriasiform reactions or HS, in patients during a treatment of rheumatoid arthitis or IBD mainly. A few reports have been described an exacerbation of psoriasis1, palmoplantar pustular, or pustular psoriasis eruption with secukinumab. Marasca et al. highlights the immunological comperformed to evaluate its efficacy and safety in moderate-to-severe HS, which will presumably be completed on January 2019. Hidradenitis suppurativa has also been reported to be paradoxically induced in patients treated with TNFα blockers, such infliximab or adalimumab (Delobeau et al., 2016). In a recently published series of 25 cases (Faivre et al., 2016), complete resolution of paradoxical hidradenitis suppurativa occurred after treatment discontinuation or switching to another biological agent, whereas reintroduction of the same biological agent resulted in relapse in all cases. Few reports have been published in order to communicate a good response to secukinumab in patients diagnosed of HS (with or without overlap psoriasis) (Thorlacius, Theut Riis, & Jemec, 2018). Nevertheless, secukinumab can also be the trigger of a paradoxical HS, as the case reported. Marasca (Marasca et al., 2019) highlights the immunological complexity that may surround autoinflammatory diseases showing the potential double pathophysiological face of secukinumab in HS, describing a case of secukinumab-induced HS and a case of HS provoked by adalimumab treatment and controlled with secukinumab therapy. The activation of interferon type I or IL-1β, and others local cytokine balance modifications, may explain the occurrence of paradoxical HS. This hypothesis is mainly focused on treatments based on TNF blockers. A possible explanation would be an increasing of the concentration of TNF-alpha, IL-26, IL-29, and IFN-γ produced by T-cells, accompanied by the increasing of IL-12 and IL-23 produced by dendritic cells. The possible magnification of ICAM-1 and TGF-B signaling, would trigger hyperproliferative keratinocytes, and as a result, HS lesions. Real world evidence and results from randomized clinical trials with secukinumab for HS, will shed light on the real and main role that anti-IL-17 drugs play in this complex disease. From clinical and immunological HS context, new therapeutic frontiers will be opened providing useful information to improve the knowledge of the immunological pathways that cause it. ORCID Francisco J. Navarro-Triviño https://orcid.org/0000-0002-5454-3671Ricardo Ruiz-Villaverde https://orcid.org/0000-0002-0381-6174

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