KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide. HCC is refractory to many standard cancer treatments and the prognosis is often poor, highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments. Kinesin family member 2C (KIF2C) is reported to be highly expressed in several human tumors. Nevertheless, the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated. In this study, we found that KIF2C expression was significantly upregulated in HCC, and that KIF2C up-regulation was associated with a poor prognosis. Utilizing both gain and loss of function assays, we showed that KIF2C promoted HCC cell proliferation, migration, invasion, and metastasis both in vitro and in vivo. Mechanistically, we identified TBC1D7 as a binding partner of KIF2C, and this interaction disrupts the formation of the TSC complex, resulting in the enhancement of mammalian target of rapamycin complex1 (mTORC1) signal transduction. Additionally, we found that KIF2C is a direct target of the Wnt/β-catenin pathway, and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORC1 signaling. Thus, the results of our study establish a link between Wnt/β-catenin and mTORC1 signaling, which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.

Prognostic significance of CUEDC2 expression in hepatocellular carcino-ma / 中国病理生理杂志

AIM:To investigate the expression of CUE domain-containing 2 (CUEDC2) in hepatocellular car-cinoma ( HCC) and to analyze its clinical prognostic significance .METHODS:Total 186 formalin-fixed paraffin-embed-ded tissues obtained from surgical HCC with detailed clinicopathological and follow -up data were used .The expression of CUEDC2 was detected by immunohistochemistry .The relationships between the expression of CUEDC 2 and clinicopatholog-ical characteristics and prognosis were analyzed .RESULTS: The positive rate of CUEDC 2 in HCC was 85.5% ( 159/186), among which, the low expression was 52.2%(97/186) and the high expression was 47.8%(89/186).CUEDC2 expression was correlated with serum alpha-fetal protein (AFP) level, tumor size, tumor number, tumor differentiation and TNM stage (P<0.05).Kaplan-Meier survival curves showed that the patients with high expression of CUEDC 2 were asso-ciated with significantly shorter overall survival and recurrence-free survival than those with low CUEDC 2 expression ( P<0.05).Multivariate Cox regression analysis revealed 3 independent prognostic factors including CUEDC 2 expression, ser-um AFP and tumor number .CONCLUSION:CUEDC2 was expressed in most HCC tissues , which was relevant to tumor growth, tumor differentiation and prognosis .CUEDC2 could be a novel valuable molecular marker to predict the HCC prog-nosis.

The propensity for tumorigenesis in human induced pluripotent stem cells is related with genomic instability / 癌症

The discovery of induced pluripotent stem cells(iPSCs) is a promising advancement in the field of regenerative medicine. Previous studies have indicated that the teratoma-forming propensity of iPSCs is variable; however, the relationship between tumorigenic potential and genomic instability in human iPSCs (HiPSCs) remains to be fully elucidated. Here, we evaluated the malignant potential of HiPSCs by using both colony formation assays and tumorigenicity tests. We demonstrated that HiPSCs formed tumorigenic colonies when grown in cancer cell culture medium and produced malignancies in immunodeficient mice. Furthermore, we analyzed genomic instability in HiPSCs using whole-genome copy number variation analysis and determined that the extent of genomic instability was related with both the cells' propensity to form colonies and their potential for tumorigenesis. These findings indicate a risk for potential malignancy of HiPSCs derived from genomic instability and suggest that quality control tests, including comprehensive tumorigenicity assays and genomic integrity validation, should be rigorously executed before the clinical application of HiPSCs. In addition, HiPSCs should be generated through the use of combined factors or other approaches that decrease the likelihood of genomic instability.

Human KIAA1018/FAN1 nuclease is a new mitotic substrate of APC/C(Cdh1) / 癌症

A recently identified protein, FAN1 (FANCD2-associated nuclease 1, previously known as KIAA1018), is a novel nuclease associated with monoubiquitinated FANCD2 that is required for cellular resistance against DNA interstrand crosslinking (ICL) agents. The mechanisms of FAN1 regulation have not yet been explored. Here, we provide evidence that FAN1 is degraded during mitotic exit, suggesting that FAN1 may be a mitotic substrate of the anaphase-promoting cyclosome complex (APC/C). Indeed, Cdh1, but not Cdc20, was capable of regulating the protein level of FAN1 through the KEN box and the D-box. Moreover, the up- and down-regulation of FAN1 affected the progression to mitotic exit. Collectively, these data suggest that FAN1 may be a new mitotic substrate of APC/CCdh1 that plays a key role during mitotic exit.