Emerging roles of CCM genes during tumorigenesis with potential application as novel biomarkers across major types of cancers

Abstract

Cerebral cavernous malformations (CCMs) are microvascular anomalies in the brain that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs: cerebral cavernous malformations 1 [(CCM1) also termed Krev interaction trapped 1 (KRIT1)], cerebral cavernous malformation 2 [(CCM2) also termed MGC4607] and cerebral cavernous malformation 3 [(CCM3) also termed programmed cell death 10 (PDCD10)]. It has been demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) with which to modulate multiple signaling cascades. CCM proteins have been reported to play major roles in microvascular angiogenesis in human and animal models. However, CCM proteins are ubiquitously expressed in all major tissues, suggesting an unseen broader role of the CSC in biogenesis. Recent evidence suggests the possible involvement of the CSC complex during tumorigenesis; however, studies concerning this aspect are limited. This is the first report to systematically investigate the expression patterns of CCM proteins in major human tumors using real-time quantitative PCR, RNA-fluorescence in situ hybridization, immunohistochemistry and multicolor immunofluorescence imaging. Our data demonstrated that differential expression patterns of the CSC complex are correlated with certain types and grades of major human cancers, indicating the potential application of CCM genes as molecular biomarkers for clinical oncology. Our data strongly suggest that more efforts are needed to elucidate the role of the CSC complex in tumorigenesis, which may have enormous clinical potential for cancer diagnostic, prognostic and therapeutic applications.

CmP signaling network unveils novel biomarkers for triple negative breast cancer in African American women

“…Non-classic mPRs are widely expressed in breast cancer cell lines and biopsies, regardless of nPR (+/-) subtype (Dressing et al, 2012;Dressing and Thomas, 2007;Pang and Thomas, 2011;Xie et al, 2012;Zuo et al, 2010). Overexpression of major mPRs (PAQR7, PAQR8, and PAQR5) has been associated with breast cancer development and progression (Dressing et al, 2012;Dressing and Thomas, 2007), as well as other reproductive tumors, such as cervical and ovarian cancer (Charles et al, 2010;Romero-Sanchez et al, 2008;Thomas, 2008) and has also been detected in diverse epithelial human ovarian cancer biopsies (Romero-Sanchez et al, 2008) and the HeLa cervical cancer cell line (Thomas, 2008), suggesting a potential role for mPRs in reproductive tumor biology (Abou-Fadel et al, 2020c;Dressing and Thomas, 2007). Our data certainly provide more evidence in supporting these views (Fig.…”

“…The copyright holder for this preprint (which this version posted May 25, 2021. ; https://doi.org/10.1101/2021.05.24.445510 doi: bioRxiv preprint TNBC cell performance is determined by the CmP network under steroid actions TNBC cell performance is determined by the CmP signaling network. Based on our previous findings, under sterol actions, the intricate balance among key players of the CmPn signaling network is achieved through a balance between the negative effects of PRG/MIF signaling via mPRs and the positive effects of PRG through nPRs signaling in nPR(+) breast cancer cells (Abou-Fadel et al, 2020b;Abou-Fadel et al, 2020c). Our goal is to investigate the more fragile relationship within the CmP signaling network on the motility of nPR(-) breast cancer cells by tipping the delicate balance of the CmP network under steroid actions.…”

CCM signaling complex (CSC) coupling both classic and non-classic progesterone receptor signaling

“…We recently identified differential expression patterns of the CSC complex are correlated with certain types and grades of major human cancers, especially in breast cancer (10,12,13), further validating a role for the CSC in tumorigenesis. To further delineate the role of not only the CSC, but also the role of classic and non-classic PRG receptors under hormone treatments, we compared our two omic approaches to identify altered signaling pathways at both the transcriptional and translational levels.…”

Disrupting the CmP signaling network unveils novel biomarkers for triple negative breast cancer in Caucasian American women

“…Briefly, nPR(-) MDA-MB-231 cells were cultured in RPMI1640 medium following manufacturer’s instructions (ATCC), and once cells reached 80% confluency, cells were starved with FBS-free RPMI1640 medium for 3 hrs, followed with either vehicle control (ethanol/DMSO, VEH) or combined steroids (MIF+PRG, 20 µM each). After cells were treated, they were harvested for RNA and protein extraction as described before [118, 119].…”