Title Page
Title:
Centromere Protein M promotes cell proliferation in hepatocarcinoma through dual regulation of cell cycle-related regulators.
Authors and Affiliations:
d Department of Thyroid and Breast Surgery, Nanshan District People’s Hospital, Shenzhen 518000, China
*Corresponding author:
ABSTRACT
Cancer is characterized by the aberrant cell cycle progression. Centromere protein M (CENPM) plays vital roles in ensuring correct separation of chromosomes during cell cycle. However, the role of CENPM in human cancers remains unknown. We examined the expression of CENPM in the TCGA database and found that CENPM was up-regulated in most of human cancers, including hepatocarcinoma (HCC). Western blotting and qRT-PCR confirmed that the expression of CENPM in HCC tissues was evaluated. The HCC patients with high CENPM expressions performed a worse survival. Multivariate Cox regression analysis revealed that the expression of CENPM was an independent prognosis factor of HCC patients. Silencing CENPM induced G2/M phase arrest and decreased the proliferation ability of HCC cells in vitro and in vivo. Conversely, overexpression of CENPM promoted the proliferation of HCC cells. Western blotting indicated that CENPM activated ERK1/2-Cyclin E pathway and repressed Cip/kip family members (p21, p27 and p57) expressions. Together, our data suggest that CENPM plays a significant role in driving HCC tumorigenesis, which may provide a potential prognostic biomarker and therapy target for HCC patients.
INTRODUCTION
Hepatocellular carcinoma (HCC), which is prevalent in Asia and Africa, is one of the most common malignant neoplasms and the third leading cause of cancer-related deaths in the world.[1]. Currently, surgical resection and orthotropic liver transplantation are the best treatment strategies for HCC patients in the early stage. [2]. However, the 5-year overall survival of HCC patients is still unsatisfactory, because most of the patients are in the late stage once been diagnosed and are ineligible for the surgical and liver transplantation.[3, 4]. The mechanisms underlying HCC progression are largely unknown. Therefore, molecular study to identify the HCC patients at high risk of poor clinical outcomes and provide the therapeutic target is a critical way to improve the survival of HCC.
Cell cycle is a highly organized and regulated process in mammalian cell that contains four distinct phases (G0/G1, S, G2 and M) [5]. Cyclin-dependent kinases (CDKs), Cyclins and CDK inhibitors (CKIs) are important regulators which are responsible for DNA replication, chromosome segregation and cell cycle progression [6]. Cancer is characterized by the uncontrolled cell proliferation, which is resulted from mutations in genes encoding cell cycle proteins or aberrant activations of the cell cycle-related signaling pathways [7, 8].In HCC, many cell cycle regulators, like CCND1 and p53, are aberrantly expressed [9, 10]. However, the molecular regulation networks involved in HCC cell cycle remain to be clarified.
Faithful division of chromosome is a key step during cell cycle progression and depends on the correctly composition of kinetochore. Kinetochore is a multi-subunit layered structure with multiple copies of many proteins, and the inner layer is composed of centromere proteins (CENPs). CENPs could interact with the outer kinetochore to maintain the centromere identity at every new cell division cycle [11]. Aberrantly expressions of CENPs have been found in many human cancers, such as breast cancer, lung cancer and HCC [12-14]. CENPM is a newly identified member of CENPs family and plays an essential role in assembling and stabilizing the CENP-HIKM complex [15]. However, the biological function of CENPM in cancer cells still unknown.In the present study, to explore the molecular roles of CENPM in HCC, we firstly analyzed the expression level of CENPM in the TCGA database and found that CENPM is upregulated in most of human cancers, including HCC. Furthermore, we verified the expression levels of CENPM in the paired HCC tissues and immortalized cell lines, and analyzed its relationship with HCC patients’ clinical features. Moreover, we explored the biological function and molecular mechanisms of CENPM in the carcinogenesis of HCC. Thus, our findings of the roles of CENPM in HCC may provide a promising prognostic biomarker and therapeutic target for HCC patients.
Title:
Centromere Protein M promotes cell proliferation in hepatocarcinoma through dual regulation of cell cycle-related regulators.
Authors and Affiliations:
d Department of Thyroid and Breast Surgery, Nanshan District People’s Hospital, Shenzhen 518000, China
*Corresponding author:
ABSTRACT
Cancer is characterized by the aberrant cell cycle progression. Centromere protein M (CENPM) plays vital roles in ensuring correct separation of chromosomes during cell cycle. However, the role of CENPM in human cancers remains unknown. We examined the expression of CENPM in the TCGA database and found that CENPM was up-regulated in most of human cancers, including hepatocarcinoma (HCC). Western blotting and qRT-PCR confirmed that the expression of CENPM in HCC tissues was evaluated. The HCC patients with high CENPM expressions performed a worse survival. Multivariate Cox regression analysis revealed that the expression of CENPM was an independent prognosis factor of HCC patients. Silencing CENPM induced G2/M phase arrest and decreased the proliferation ability of HCC cells in vitro and in vivo. Conversely, overexpression of CENPM promoted the proliferation of HCC cells. Western blotting indicated that CENPM activated ERK1/2-Cyclin E pathway and repressed Cip/kip family members (p21, p27 and p57) expressions. Together, our data suggest that CENPM plays a significant role in driving HCC tumorigenesis, which may provide a potential prognostic biomarker and therapy target for HCC patients.
INTRODUCTION
Hepatocellular carcinoma (HCC), which is prevalent in Asia and Africa, is one of the most common malignant neoplasms and the third leading cause of cancer-related deaths in the world.[1]. Currently, surgical resection and orthotropic liver transplantation are the best treatment strategies for HCC patients in the early stage. [2]. However, the 5-year overall survival of HCC patients is still unsatisfactory, because most of the patients are in the late stage once been diagnosed and are ineligible for the surgical and liver transplantation.[3, 4]. The mechanisms underlying HCC progression are largely unknown. Therefore, molecular study to identify the HCC patients at high risk of poor clinical outcomes and provide the therapeutic target is a critical way to improve the survival of HCC.
Cell cycle is a highly organized and regulated process in mammalian cell that contains four distinct phases (G0/G1, S, G2 and M) [5]. Cyclin-dependent kinases (CDKs), Cyclins and CDK inhibitors (CKIs) are important regulators which are responsible for DNA replication, chromosome segregation and cell cycle progression [6]. Cancer is characterized by the uncontrolled cell proliferation, which is resulted from mutations in genes encoding cell cycle proteins or aberrant activations of the cell cycle-related signaling pathways [7, 8].In HCC, many cell cycle regulators, like CCND1 and p53, are aberrantly expressed [9, 10]. However, the molecular regulation networks involved in HCC cell cycle remain to be clarified.
Faithful division of chromosome is a key step during cell cycle progression and depends on the correctly composition of kinetochore. Kinetochore is a multi-subunit layered structure with multiple copies of many proteins, and the inner layer is composed of centromere proteins (CENPs). CENPs could interact with the outer kinetochore to maintain the centromere identity at every new cell division cycle [11]. Aberrantly expressions of CENPs have been found in many human cancers, such as breast cancer, lung cancer and HCC [12-14]. CENPM is a newly identified member of CENPs family and plays an essential role in assembling and stabilizing the CENP-HIKM complex [15]. However, the biological function of CENPM in cancer cells still unknown.In the present study, to explore the molecular roles of CENPM in HCC, we firstly analyzed the expression level of CENPM in the TCGA database and found that CENPM is upregulated in most of human cancers, including HCC. Furthermore, we verified the expression levels of CENPM in the paired HCC tissues and immortalized cell lines, and analyzed its relationship with HCC patients’ clinical features. Moreover, we explored the biological function and molecular mechanisms of CENPM in the carcinogenesis of HCC. Thus, our findings of the roles of CENPM in HCC may provide a promising prognostic biomarker and therapeutic target for HCC patients.
