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. 2018 Jun 18;16(1):109.
doi: 10.1186/s12957-018-1375-9.

Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis

Rui Zhang  1 , Tong-Tong Zhang, Gao-Qiang Zhai  1 , Xian-Yu Guo  1 , Yuan Qin  1 , Ting-Qing Gan  2 , Yu Zhang  1 , Gang Chen  1 , Wei-Jia Mo  3 , Zhen-Bo Feng  4
Affiliations

Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis

Rui Zhang et al. World J Surg Oncol. .

Abstract

Background: This study was carried out to discover the underlying role that HOXA11 plays in lung squamous cancer (LUSC) and uncover the potential corresponding molecular mechanisms and functions of HOXA11-related genes.

Methods: Twenty-three clinical paired LUSC and non-LUSC samples were utilized to examine the level of HOXA11 using quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of HOXA11 was systematically analyzed based on 475 LUSC and 18 non-cancerous adjacent tissues from The Cancer Genome Atlas (TCGA) database. A total of 102 LUSC tissues and 121 non-cancerous tissues were available from Oncomine to explore the expressing profiles of HOXA11 in LUSC. A meta-analysis was carried out to further assess the differential expression of HOXA11 in LUSC, including in-house qRT-PCR data, expressing data extracted from TCGA and Oncomine databases. Moreover, the enrichment analysis and potential pathway annotations of HOXA11 in LUSC were accomplished via Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of hub genes and according correlations with HOXA11 were assessed to further explore the biological role of HOXA11 in LUSC.

Results: HOXA11 expression in LUSC had a tendency to be upregulated in comparison to adjacent non-cancerous tissues by qRT-PCR. TCGA data displayed that HOXA11 was remarkably over-expressed in LUSC compared with that in non-LUSC samples, and the area under curves (AUC) was 0.955 (P < 0.001). A total of 1523 co-expressed genes were sifted for further analysis. The most significant term enriched in the KEGG pathway was focal adhesion. Among the six hub genes of HOXA11, including PARVA, ILK, COL4A1, COL4A2, ITGB1, and ITGA5, five (with the exception of COL4A1) were significantly decreased compared with the normal lung tissues. Moreover, the expression of ILK was negatively related to HOXA11 (r = - 0.141, P = 0.002).

Conclusion: High HOXA11 expression may lead to carcinogenesis and the development of LUSC. Furthermore, co-expressed genes might affect the prognosis of LUSC.

Keywords: Clinical features; Enrichment analysis; HOXA11; Lung squamous cancer; qRT-PCR.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ethical Committee of the First Affiliated Hospital of Guangxi Medical University. Ethics, consent, and permissions: Written informed consents were signed by all the patients involved to ensure their approval of the data used in this research.

Consent for publication

All the patients signed the agreement consents for publishing their individual clinical data.

Competing interests

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Data analysis of qRT-PCR. a The expression of HOXA11 in 23 LUSC and paired non-cancerous lung tissues. (b) The AUC of the TNM stage from the results of in-house qRT-PCR was 0.831 (P = 0.008)
Fig. 2
Fig. 2
Data analysis of TCGA. a HOXA11 expressed higher in LUSC (5.531 ± 2.054) than that in non-cancer tissues (1.209 ± 0.813) from TCGA (P < 0.001). b The AUC of HOXA11 for diagnosing LUSC was 0.955 (P < 0.001). c The OS of LUSC patients (P = 0.795). d The DFS of LUSC patients (P = 0.864)
Fig. 3
Fig. 3
Data analysis of five studies extracted from Oncomine. a HOXA11 expressed higher in LUSC in Hou’s study (P = 0.002). b HOXA11 was higher in LUSC tissues in Garber’s study (P = 0.007). c HOXA11 expressed insignificant in Wachi’s study (P = 0.318). d HOXA11 showed no significant results in Bhattacharjee’s study (P = 0.224). e HOXA11 decreased in LUSC in Talbot’s study (P = 0.003). f The AUC of HOXA11 for diagnosing LUSC in Hou’s study was 0.717 (P = 0.001). g The AUC of HOXA11 for diagnosing LUSC in Garber’s study was 0.781 (P = 0.047). h The AUC of HOXA11 for diagnosing LUSC in Wachi’s study was 0.720 (P = 0.251). i The AUC of HOXA11 for diagnosing LUSC in Bhattacharjee’s study was 0.753 (P = 0.009). j The AUC of HOXA11 for diagnosing LUSC in Talbot’s study was 0.744 (P = 0.001)
Fig. 4
Fig. 4
Analysis of pooled expressing profiles of HOXA11 in LUSC. a The expression of HOXA11 in 762 samples (600 LUSC and 162 non-cancerous lung tissues) from in-house qRT-PCR, TCGA, and Oncomine. b The AUC of HOXA11 for diagnosing LUSC was 0.873 (P < 0.0001). c The forest plots of HOXA11 levels in LUSC
Fig. 5
Fig. 5
Diagrams of Venn and alterations of HOXA11 in LUSC. a The counts of intersected genes from MEM, cBioPortal, and GEPIA databases. b The alterative conditions of HOXA11 in LUSC obtained from the Oncomine database. Amplification and mRNA upregulation occurred on one patient at the same time
Fig. 6
Fig. 6
Top 10 significant pathways and GO enrichment analysis. a Graph of the 10 most significant pathways of BP category. b Enrichment analysis of BP, each node means one different function and more significant ones are filled in with a deeper color. c Top 10 significant terms in the CC category. d Enrichment analysis of the CC category; each node means one different function, and more significant ones are filled in with a deeper color. e Ten most valuable annotations of the MF category. f Enrichment analysis of the CC category; each node means one different function, and more significant ones are filled in with a deeper color
Fig. 7
Fig. 7
Interactions between different pairs of proteins. Nodes represent various symbols of genes; edges represent protein-protein associations
Fig. 8
Fig. 8
Hub genes’ expression in LUSC and correlations with HOXA11. a ILK was lower in LUSC tissues than in non-cancerous tissues (P < 0.001). b The gene PARVA was significantly overexpressed in normal tissues (P < 0.001). c The levels of COL4A1 in different tissues showed no significance (P = 0.061). d The hub gene ITGB1 revealed higher levels in normal tissues (P < 0.001). e ITGA5 was significantly decreased in LUSC tissues (P < 0.001). f COL4A2 upregulated in non-LUSC tissues (P < 0.001). g ILK and HOXA11 showed a negative correlation (r = − 0.141, P = 0.002). h Correlations between PARVA and HOXA11 showed no significance (P = 0.645). i Correlations between COL4A1 and HOXA11 showed no significance (P = 0.337). j Correlations between ITGB1 and HOXA11 showed no significance (P = 0.936). k Correlations between ITGA5 and HOXA11 showed no significance (P = 0.501). l Correlations between COL4A2 and HOXA11 showed no significance (P = 0.248)
Fig. 9
Fig. 9
The protein level of the selected hub genes in LUSC tissues from The Human Protein Atlas. a ILK (Antibody CAB004041) expression in LUSC tissues. b PARVA (Antibody HPA005964) expression in LUSC tissues. c COL4A1 (Antibody CAB001695) expression in LUSC tissues. d ITGB1 (Antibody CAB003434) expression in LUSC tissues. e ITGA5 (Antibody CAB009008) expression in LUSC tissues. f COL4A2 (Antibody CAB010751) expression in LUSC tissues
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