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. 2022 Nov 15;14(11):2138-2156.
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  1 , Chun-Lan Li  1 , Zheng Wu  1 , Yan-Yu Hou  1 , Hua-Tao Wu  2 , Jing Liu  3
Affiliations

Comprehensive analysis of the potential role and prognostic value of sine oculis homeobox homolog family in colorectal cancer

Ze-Xuan Fang et al. World J Gastrointest Oncol. .

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 χ 2 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: Colorectal cancer; Development; Expression; Prognostic indicator; Sine oculis homeobox homolog; Treatment.

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Conflict of interest statement

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Figures

Figure 1
Figure 1
Sine oculis homeobox homologs in different cancerous tissues and corresponding normal tissues in the Tumor Immune Estimation Resource 2.0 database. A: Sine oculis homeobox homolog (SIX)1; B: SIX2; C: SIX3; D: SIX4; E: SIX5; F: SIX6. aP < 0.05, bP < 0.01, cP < 0.001. SIX: Sine oculis homeobox homolog; TPM: Transcript count per million.
Figure 2
Figure 2
Expression of sine oculis homeobox homolog family members in The Cancer Genome Atlas colon and rectal cancer tissues in the UCSC Xena database. Red: Normal tissue; Blue: Cancerous tissue. One-way analysis of variance was utilized for statistical significance. cP < 0.001. SIX: Sine oculis homeobox homolog; TCGA: The Cancer Genome Atlas.
Figure 3
Figure 3
Overall survival of colorectal cancer patients estimated by individual expression of sine oculis homeobox homolog family members. A: Sine oculis homeobox homolog (SIX)1; B: SIX2; C: SIX3; D: SIX4; E: SIX5; F: SIX6. HR: Hazard ratio; SIX: Sine oculis homeobox homolog.
Figure 4
Figure 4
Disease-free survival of colorectal cancer patients estimated by individual expression of sine oculis homeobox homolog family members. A: Sine oculis homeobox homolog (SIX)1; B: SIX2; C: SIX3; D: SIX4; E: SIX5. SIX: Sine oculis homeobox homolog.
Figure 5
Figure 5
Sine oculis homeobox homolog 4-associated genes. A: All associated genes; B: Top 50 positively-correlated genes; C: Top 50 negatively-correlated genes. SIX4: Sine oculis homeobox homolog 4.
Figure 6
Figure 6
Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses of sine oculis homeobox homolog 4-associated genes. A: Kyoto Encyclopedia of Genes and Genomes; B: Biological process; C: Cellular component; D: Molecular function.
Figure 7
Figure 7
Relationship between sine oculis homeobox homolog 4 level and clinicopathological parameters of colorectal cancer patients. A: Tumor size; B: Lymph node status; C: Metastasis; D: Stage. SIX: Sine oculis homeobox homolog.
Figure 8
Figure 8
Representative sine oculis homeobox homolog 4 staining in colorectal cancer and adjacent normal tissues from a patient. A: Colorectal cancer tissue; B: Adjacent normal tissue.
Figure 9
Figure 9
Kaplan-Meier analysis of sine oculis homeobox homolog 4 expression on overall survival of colorectal cancer patients. SIX: Sine oculis homeobox homolog.
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