SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive type of cancer of the thoracic cavity commonly associated with asbestos exposure and a high mortality rate. There is a need for new molecular targets for the development of more effective therapies for MPM. Using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and an RNA interference-based screening, we examined the SORORIN gene as potential therapeutic targets for MPM in addition to the PLK1 gene, which is known for kinase of SORORIN. Following in vitro investigation of the effects of target silencing on MPM cells, cell cycle analyses were performed. SORORIN expression was analyzed immunohistochemically using a total of 53 MPM samples on tissue microarray. SORORIN was found to be overexpressed in the majority of clinical MPM samples and human MPM cell lines as determined by qRT-PCR. Gene suppression of each SORORIN and PLK1 led to growth inhibition in MPM cell lines. Knockdown of SORORIN showed an increased number of G2M-phase population and a larger nuclear size, suggesting mitotic arrest. High expression of SORORIN (SORORIN-H) was found in 50.9% of all the MPM cases, and there is a tendency towards poorer prognosis for the SORORIN-H group but the difference is not significant. Suppression of SORORIN with PLK1 inhibitor BI 6727 showed a combinational growth suppressive effect on MPM cell growth. Given high-dose PLK1 inhibitor induced drug-related adverse effects in several clinical trials, our results suggest inhibition SORORIN-PLK1 axis may hold promise for the treatment of MPMs.

CDCA5 functions as a tumor promoter in bladder cancer by dysregulating mitochondria-mediated apoptosis, cell cycle regulation and PI3k/AKT/mTOR pathway activation

“…CDCA5 also maintains cohesion in chromatin to ensure its maturity and keeps sister chromatids together during mitosis [10]. Multiple studies have revealed that CDCA5 is overexpressed in various cancers, such as lung cancer, oral squamous cell carcinoma, gastric cancer, pleural mesothelioma and hepatocellular carcinoma, and acts as a tumor promoter [15,[17][18][19][20]. Although there was a study that showed that CDCA5 overexpression is associated with advanced clinical features and poor prognosis of urothelial carcinoma, the underlying mechanisms of how CDCA5 promotes the tumorigenicity of BC remain unclear.…”

“…In the G1 phase, the CDCA5 protein is degraded through Cdc20 homolog 1 (Cdh1)-activated APC (APC cdh1 )dependent ubiquitination. Recent studies have reported that CDCA5 is overexpressed in some tumor tissues, suggesting that it may act as a promoter in tumor progression [15][16][17][18][19][20]. Although high CDCA5 expression is associated with advanced stages in various tumors, the role of CDCA5 in BC development and progression is not fully defined.…”

CDCA5 regulates proliferation in hepatocellular carcinoma and has potential as a negative prognostic marker

“… 13 – 17 CDCA5 knockdown experiments confirm associations of CDCA5 with cell cycle progression at the G2/M phase checkpoint and show significant suppression of tumor growth in the absence of CDCA5. 11 , 12 , 18 Clinical studies also show significantly increased CDCA5 expression in various tumor tissues and demonstrate correlations with poor prognosis. 9 – 12 Hence, CDCA5 likely plays specific roles in tumor progression and is a potential biological marker of prognosis that may be targeted using molecular therapies.…”

A gene‑expression‑based test can outperform bap1 and p16 analyses in the differential diagnosis of pleural mesothelial proliferations

“…On the other hand, the MPM tool is highly reproducible, and almost completely automatized (14,25). It could also be even more informative, due to the inclusion of genes with a crucial role in cancer development, and progression (14); some of which also correlate with MPM prognosis and are potential therapeutic targets (26,27).…”