KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3.

Yanhong Wang,Yongli Bao,Yanping Zheng,Muqing Zhang,Ying Sun,Zhenbo Song,Anqing Wang,Guannan Wang,Shuyue Wang,Lei Liu,Lihua Zheng,Jingwen Yi,Chunlei Yu,Na Li,Yanxin Huang,Luguo Sun

doi:10.3390/ijms23010104

Abstract

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

Highlights

Cancer is a disease that seriously threatens human life and health worldwide [1].The occurrence and development of cancer is a complex multistep process involving the accumulation of multiple genetic and epigenetic changes that lead to alterations in a large number of tumor-related genes, such as the activation of oncogenes and the inactivation of tumor suppressor genes [2,3]
Tumor invasion and metastasis are the main causes of a poor prognosis and cancer-related death, effective strategies that suppress cancer metastasis are still lacking in the clinic [30]
We showed for the first time that KIAA1217, a macromolecular protein with an unknown function, significantly promoted hepatocellular carcinoma (HCC) metastasis by inducing epithelial-mesenchymal transition (EMT)

Summary

Introduction

The occurrence and development of cancer is a complex multistep process involving the accumulation of multiple genetic and epigenetic changes that lead to alterations in a large number of tumor-related genes, such as the activation of oncogenes and the inactivation of tumor suppressor genes [2,3]. Cancer is still insufficiently understood due to its complexity, which hinders efforts to achieve a complete cure of cancer. Further explorations of the molecular mechanism underlying the occurrence and development of cancer, such as discovering the role of more tumor-related genes in the progression of cancer, are still indispensable. KIAA1217, the human homolog of murine Skt (sickle tail), was identified in the large HUGE (human unidentified gene-encoded) protein database [4] and is a macromolecular protein with an unknown function.

Methods

Results

Conclusion