Basic Study
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World J Gastrointest Oncol. Nov 15, 2022; 14(11): 2138-2156
Published online Nov 15, 2022. doi: 10.4251/wjgo.v14.i11.2138
Comprehensive analysis of the potential role and prognostic value of sine oculis homeobox homolog family in colorectal cancer
Ze-Xuan Fang, Chun-Lan Li, Zheng Wu, Yan-Yu Hou, Hua-Tao Wu, Jing Liu
Ze-Xuan Fang, Chun-Lan Li, Zheng Wu, Yan-Yu Hou, Jing Liu, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
Hua-Tao Wu, Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
Author contributions: Liu J and Wu HT designed the research study; Fang ZX performed the research; Fang ZX, Li CL, Wu Z, Hou YY and Wu HT analyzed the research and wrote the manuscript; Liu J revised the manuscript critically; and all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81501539; the Natural Science Foundation of Guangdong Province, No. 2021A1515012180 and 2016A030312008; Special Grant for Key Area Programs of Guangdong Department of Education, No. 2021ZDZX2004; Science and Technology Special Project of Guangdong Province, No. 210715216902829; “Dengfeng Project” for the construction of high-level hospitals in Guangdong Province-First Affiliated Hospital of Shantou University College Supporting Funding, No. 202003-10.
Institutional review board statement: The current study was reviewed and approved by the Ethics Committee of Shantou University Medical College.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
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: Jing Liu, MD, PhD, Academic Research, Associate Professor, Research Scientist, Senior Scientist, Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, No. 22 Xinling Road, Shantou 515041, Guangdong Province, China. jliu12@stu.edu.cn
Received: July 9, 2022
Peer-review started: July 9, 2022
First decision: July 31, 2022
Revised: August 30, 2022
Accepted: October 31, 2022
Article in press: October 31, 2022
Published online: November 15, 2022
Processing time: 128 Days and 16.4 Hours
Abstract
BACKGROUND

Several genes, important for development, are reduced or silenced in adulthood, and their abnormal expression has been related to the occurrence and development of malignant tumors. Human sine oculis homeobox homolog (SIX) proteins belong to the homeobox family and play important roles in the development of different organs. Importantly, SIXs are predicted to have chromatin-binding and DNA-binding transcription factor activity with reported roles in cancers. However, a comprehensive analysis of SIXs in colorectal cancers (CRCs) has not been performed.

AIM

To explore the expression pattern of six SIX proteins in CRCs and their relationship with the clinicopathological parameters of CRC patients as well as investigate the potential utilization of SIXs as novel prognostic indicators in CRCs.

METHODS

The expression level of SIXs in normal tissues of different organs and related cancerous tissues was analyzed in the Human Protein Atlas. Kaplan-Meier Plotter and GEPIA2 were used to analyze the prognostic values of SIXs. To analyze the potential signaling pathways with SIX family involvement, LinkedOmics was used to perform Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of SIX4-related genes. Subsequently, immunohistochemical experiments were performed on CRC tissues and adjacent normal tissues, and we examined the SIX4 expression level in 87 pairs of patients with tissue microarray. The relationship between SIX4 and clinicopathological parameters in CRC patients was tested using the χ2 test and Fisher’s exact probability to verify the results of the database analysis.

RESULTS

The RNA levels of SIX1-4 and SIX6 were relatively low in normal human tissues, while SIX5 was highly expressed at both the RNA and protein levels. However, the protein level of SIX4 was found to be elevated in various malignancies. In CRC tissues, SIX1, SIX2 and SIX4 were elevated in cancer tissues compared with adjacent normal tissue. Among all SIXs, a high level of SIX4 was found to be associated with poor overall and disease-free survival in patients with CRC. For different clinicopathological parameters, increased SIX4 expression was positively correlated with advanced CRC. The top 50 SIX4-related genes were involved with oxidative phosphorylation and the respiratory chain signaling pathways.

CONCLUSION

The current results provided a comprehensive analysis of the expression and prognostic values of SIX family members in CRC. Among different SIXs, SIX4 plays an oncogenic role in CRC to promote the development of malignancy. In CRC, SIX4 mRNA and protein expression is higher than that in normal tissues and associated with shorter CRC patient survival, suggesting that SIX4 may be a potential therapeutic target for treatment of CRC patients.

Keywords: Sine oculis homeobox homolog, Colorectal cancer, Development, Treatment, Expression, Prognostic indicator

Core Tip: This study systematically analyzed the expression pattern and prognostic value of sine oculis homeobox homolog (SIX) family members in colorectal cancer (CRC). It was found that the expression of SIX4 in CRC tissues positively correlated with the development of CRC and negatively correlated with overall survival. The top 50 SIX4-related genes were involved with oxidative phosphorylation and the respiratory chain signaling pathways. SIX4 may be a novel and potential therapeutic target for CRC.