A systematic analysis of orphan cyclins reveals CNTD2 as a new oncogenic driver in lung cancer

Abstract

As lung cancer has increased to the most common cause of cancer death worldwide, prognostic biomarkers and effective targeted treatments remain lacking despite advances based on patients’ stratification. Multiple core cyclins, best known as drivers of cell proliferation, are commonly deregulated in lung cancer where they may serve as oncogenes. The recent expansion of the cyclin family raises the question whether new members might play oncogenic roles as well. Here, we investigated the protein levels of eight atypical cyclins in lung cancer cell lines and formalin-fixed and paraffin-embedded (FFPE) human tumors, as well as their functional role in lung cancer cells. Of the new cyclins evaluated, CNTD2 was significantly overexpressed in lung cancer compared to adjacent normal tissue, and exhibited a predominant nuclear location. CNTD2 overexpression increased lung cancer cell viability, Ki-67 intensity and clonogenicity and promoted lung cancer cell migration. Accordingly, CNTD2 enhanced tumor growth in vivo on A549 xenograft models. Finally, the analysis of gene expression data revealed a high correlation between elevated levels of CNTD2 and decreased overall survival in lung cancer patients. Our results reveal CNTD2 as a new oncogenic driver in lung cancer, suggesting value as a prognostic biomarker and therapeutic target in this disease.

Atypical cyclins: the extended family portrait

“…We believe that the name atypical is the one that more accurately reflects the particularities of these cyclins and has already been used by several groups [66,81,103,108,109]. Other names, such as "new cyclins" [110] or "orphan cyclins" [67,111], are not recommended given that after all these years, they can hardly be considered new, whereas some previously orphan cyclins have now known CDK partners.…”

“…Moreover, a closer look at this subfamily may unravel novel strategies to fight cancer. In this regard, our group has recently assigned an oncogenic role to CNTD2/ CCNP in colon and lung cancers [67,81]. Given that CCNP is overexpressed in several cancers and poorly expressed in tissues, it may represent the ideal target candidate.…”

“…The prosurvival function of the CCNI-CDK5 complex was shown to occur via MEK/ERK pathway activation and upregulation of antiapoptotic Bcl-2 and Bcl-XL [66]. CCNI has also been shown to increase the proliferation of Hela and lung cancer cell lines, although it is still unclear whether these effects are mediated through the interaction with a CDK [67,68]. Accordingly, CCNI overexpression was associated with a worse prognosis in patients with lung Fig.…”

“…All the proteins containing either a Pfam domain PF00134 or PF08613 were included in the analysis. The length of the proteins, as well as the length of the domains, are on scale adenocarcinoma [67] and it was proposed that CCNI mRNA in saliva could be a biomarker for lung cancer detection [69].…”

“…Recent work from our group demonstrated that CCNP, also known as CNTD2, is overexpressed in samples from lung and colon cancer patients and promotes tumor cell proliferation and migration both in vitro and in vivo [67,81]. Further studies are now required to provide insight on the mechanisms underlying the oncogenic actions of CCNP.…”