The roles of x-linked Midline 1 interacting protein 1 (MID1IP1) in gender disparity and development of hepatocellular carcinoma

Abstract

HBV-associated hepatocellular carcinoma (HCC) has a male predominance, with a male-to-female ratio of about 5:1, suggesting gender difference is one of the major risk factors for HCC development. However, up till now, no concrete evidence is obtained to elucidate the male predominance of HCC. It is believed that the gender-specific signaling pathway is critically involved and targeting this pathway may provide a significant treatment outcome. To target candidates that are implicated in the male predominance in HCC, aberrant expression of sex-linked genes between HCC tumors and non-tumorous livers (NT-L) draws particular attention. Previously, we performed transcriptome sequencing on sixteen pairs of human HCC tumors and NT-Ls. Our preliminary data show that a potential target, Midline 1 interacting protein 1 (MID1IP1) which is involved in hepatic lipogenesis and microtubule stabilization, was remarkably overexpressed in HCC tumors as compared to the NT-Ls (fold change=2.73; p=0.017). Moreover, the expression of MID1IP1 was significantly higher in male non-tumorous liver tissue than that of female (fold change=2.63; p=0.001). In addition, the upregulation of MID1IP1 correlated with less tumor encapsulation, more tumor microsatellite formation, more venous and direct liver invasion, and poorer tumor stage, features of a more aggressive biological behavior in our clinicopathological correlation study. Moreover, upregulation of MID1IP1 in the tumors was associated with a poorer overall survival. In its functional study, upon knockdown of MID1IP1, HCC cells (BEL7402, SMMC7721 and HepG2) had reduced proliferation rates in the cell proliferation assay and colony formation assay. Here, we also showed that the migratory abilities of the HCC cell lines with MID1IP1 knockdown were remarkably reduced in the transwell assay. Furthermore, the STRING interaction network analysis suggests that MID1IP1 interacts with Suppressor of Fused (Sufu), which is a regulator of Gli in the hedgehog (HH) pathway. To examine its regulatory pathway, we showed that the mRNA expression of the negative regulator of HH pathway, Gli3, was increased in the MID1IP1 knockdown HCC cells. The downstream target of Gli, cyclin D, was also downregulated upon MID1IP1 knockdown. In summary, our data suggest that the MID1IP1 plays a significant role in the male predominance of human HCC. MID1IP1 may also play a novel role in the regulation of hedgehog signaling.