Suppression of intrahepatic cholangiocarcinoma cell growth by SKI via upregulation of the CDK inhibitor p21

Abstract

Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second-most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA-3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA-3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI-overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin-dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI-overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21-luciferase was activated in SKI-overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI-p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC.

Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Distinct Subgroups and Proteins Associated with Time-To-Recurrence

“…For example, high LDHA expression is associated with a poor prognosis, while FAM3C expression was linked to highly malignant ICC cancer stem-cells 58,59 . Considering SKI oncoprotein, two transcriptomic studies identified its role in the development of ICC 60,61 .…”

New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma

“…Figure 1B shows the currently available medications that target pathways downstream of the genes (or cell surface receptors) shown in Figure 1A. We previously reported that the Sloan Kettering Institute gene promotes expression of the cyclin-dependent kinase inhibitor tumor protein p21 (TP21) downstream of the TP53 pathway and inhibits the proliferation of intrahepatic human CC cells (Figure 1B) [19]. Precision medicine describes drugs that target specific pathways linked to identified gene mutations, and approximately 40% of BTC cases are expected to have precision medicines based on the results of tumor tissue sampling [20].…”