Liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer-related deaths worldwide. The liver is a primary metabolic organ for progesterone (PRG) and PRG exerts its effects through classic nuclear PRG receptors (nPRs) and non-classic membrane PRG receptors (mPRs) or a combination of both. Previous studies have shown that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the CmPn (CSC-mPR-PRG-nPR) signaling network, which is involved in multiple cellular signaling pathways, including tumorigenesis of various cancers. Despite advances in treatment, 5-year survival rates for liver cancer patients remain low, largely due to the chemoresistant nature of HCCs. The lack of sensitive and specific biomarkers for liver cancer diagnosis and prognosis emphasizes the need for identifying new potential biomarkers. We propose the potential use of CmPn members’ expression data as prognostic biomarkers or biomarker signatures for the major types of hepatic cancer, including HCCs and CCAs, as well as rare subtypes such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS). In this study, we investigated the CmPn network through RNAseq data and immunofluorescence techniques to measure alterations to key cancer pathways during liver tumorigenesis. Our findings reveal significant differential expression of multiple CmPn members, including CCM1, PAQR7, PGRMC1, and nPRs, in both HCCs and CCAs, highlighting the crucial roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. These key members of the CmPn network may serve as potential biomarkers for the diagnosis and prognosis of liver cancer subtypes, including rare subtypes.

Liver cancer, the sixth most diagnosed cancer worldwide is the third most common cause of cancer related deaths. The two most prevalent diagnosed subtypes include Hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CCA) which comprise about 75% and 12-15% of all liver cancer cases, respectively. The liver is known to be a primary target and metabolic organ of the sex steroid hormone progesterone (PRG), which can induce its effects through either classic nuclear PRG receptors (nPRs), non-classic membrane PRG receptors (mPRs), or combined responses. In our previous studies we have demonstrated that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the novel CmPn signaling network, which is involved in multiple cellular signaling pathways including angiogenesis and tumorigenesis of multiple cancers including breast cancers. Utilizing RNAseq data and Immunofluorescence approaches, we investigated the CmPn network to measure alterations to key cancer pathways during liver tumorigenesis by examining expression profiling for key CmPn members across multiple liver cancer subtypes, at both the transcriptional and translational levels. Our results demonstrated significant differential expression for multiple members of the CmPn signaling network including CCM1, PAQR7, PGRMC1, and nPRs, for both HCCs and CCAs, reinforcing the definitive roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. Therefore, we propose the future use of CmPn members’ expression data as potential prognostic hepatic cancer biomarkers or biomarker signatures to not only distinguish between two major subtypes, HCCs and CCAs, but also to define some rare subtypes, such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS), which may lead to hopeful new therapeutic strategies for hepatic cancers.

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