Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2022; 14(7): 1239-1251
Published online Jul 15, 2022. doi: 10.4251/wjgo.v14.i7.1239
KIFC3 promotes proliferation, migration and invasion of esophageal squamous cell carcinoma cells by activating EMT and β-catenin signaling
Wei-Wei Hao, Feng Xu
Wei-Wei Hao, Feng Xu, Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Author contributions: Hao WW designed and performed experiments, analyzed data, and wrote the article; Xu F conceived the study, analyzed the data, and revised the article; all authors have read and approved the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at the First Hospital of Zhengzhou University (No. 2021-KY-0446-001).
Institutional animal care and use committee statement: All animal research procedures were approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (No. 2021-KY-0446-001). All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978).
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Feng Xu, MD, Chief Doctor, Professor, Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan Province, China. xufengmd@sina.com
Received: November 18, 2021
Peer-review started: November 18, 2021
First decision: January 12, 2022
Revised: January 26, 2022
Accepted: March 26, 2022
Article in press: March 26, 2022
Published online: July 15, 2022
Processing time: 236 Days and 15.7 Hours
Abstract
BACKGROUND

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. A total of 45 kinesin superfamily proteins (KIFs) have been identified in humans, among which several family members have demonstrated varied functions in tumor pathobiology via different mechanisms, including regulation of cell cycle progression and metastasis. KIFC3 has microtubule motor activity and is involved in cancer cell invasion and migration, as well as survival. However, the role of KIFC3 in ESCC is still unknown.

AIM

To evaluate the role of KIFC3 in ESCC and the underlying mechanisms.

METHODS

Expression of KIFC3 was evaluated in ESCC tissues and adjacent normal esophageal tissues. The prognostic value of KIFC3 was analyzed using Kaplan–Meier Plotter. Colony formation, EdU assays, cell cycle analysis, Transwell assay, immunofluorescence, and western blotting were performed in ESCC cell lines after transfection with pLVX-Puro-KIFC3-shRNA- and pLVX-Puro-KIFC3-expressing lentiviruses. A xenograft tumor model in nude mice was used to evaluate the role of KIFC3 in tumorigenesis. Inhibitor of β-catenin, XAV-939, was used to clarify the mechanism of KIFC3 in ESCC. To analyze the differences between groups, t test and nonparametric tests were used. P < 0.05 was considered statistically significant.

RESULTS

Immunohistochemical staining indicated that KIFC3 was upregulated in ESCC tissues compared with adjacent normal tissues. Kaplan–Meier Plotter revealed that overexpressed KIFC3 was associated with poor prognosis in ESCC patients. Colony formation and EdU assay showed that KIFC3 overexpression promoted cell proliferation, while KIFC3 knockdown inhibited cell proliferation in ESCC cell lines. In addition, cell cycle analysis showed that KIFC3 overexpression promoted cell cycle progression. KIFC3 knockdown suppressed ESCC tumorigenesis in vivo. Transwell assay and western blotting revealed that KIFC3 overexpression promoted cell migration and invasion, as well as epithelial–mesenchymal transition (EMT), while KIFC3 knockdown showed the opposite results. Mechanistically, KIFC3 overexpression promoted β-catenin signaling in KYSE450 cells; however, the role of KIFC3 was abolished by XAV-939, the inhibitor of β-catenin signaling.

CONCLUSION

KIFC3 was overexpressed in ESCC and was associated with poor prognosis. Furthermore, KIFC3 promoted proliferation, migration and invasion of ESCC via β-catenin signaling and EMT.

Keywords: Esophageal squamous cell carcinoma; KIFC3; β-catenin; Cell proliferation; Cell migration; Cell invasion

Core tip: Esophageal squamous cell carcinoma (ESCC) is one of the most dangerous malignancies affecting human health. However, the mechanism of ESCC is still unclear. We revealed that KIFC3 was upregulated in ESCC. In addition, overexpressed KIFC3 was associated with poor prognosis in ESCC patients. In vitro and in vivo experiments revealed that KIFC3 promoted the proliferation, migration and invasion of ESCC cells by activating epithelial–mesenchymal transition and β-catenin signaling. Our study strongly suggests that KIFC3 may be a potential new therapeutic target for ESCC.