KIAA0101 as a new diagnostic and prognostic marker, and its correlation with gene regulatory networks and immune infiltrates in lung adenocarcinoma

Results

Differential expression of KIAA0101 in lung adenocarcinoma

Figure 1A shows a heat map of multiple genes that were overexpressed in LUAD. The top 23 ranked differentially expressed genes were obtained based on the log2 median centered ratio. After a genome-wide analysis, we identified these 23 genes, including KIAA0101, which were overexpressed in LUAD (Figure 1A, red text genes). We used Oncomine to analyze the expression distribution of KIAA0101 mRNA in different tumors (Figure 1B). Oncomine collected these datasets from public repositories such as Gene Expression Omnibus (GEO) and Array Express. The results showed that when comparing cancer samples with normal samples, KIAA0101 was overexpressed in 17 LUAD datasets, but was not under-expressed in any of the LUAD datasets (Figure 1B). The thresholds were a P value less than 0.001, fold change greater than two, and gene rank in the top 10%. All results were statistically significant. The results were analyzed statistically using Student's t test. The mRNA expression level of KIAA0101 was significantly higher in LUAD than in normal tissues. Figure 1C1–1C8 show the data from Oncomine, GEPIA, and Ualcan comparisons of KIAA0101 mRNA levels between eight different gene sets of adenocarcinoma and normal tissues. All the results showed that the expression level of KIAA0101 in LUAD tissues was significantly higher than that in normal lung tissues, as assessed using Student's t test. Further analysis of various clinical features of LUAD in the TCGA showed that KIAA0101 was highly transcribed. In subgroup analysis based on stage, race, sex, age, smoking habit, and metastasis in the UALCAN database, the transcription level of KIAA0101 in patients with LUAD was significantly higher than that in healthy people (Supplementary Figure 14A–14F). Therefore, the expression of KIAA0101 could be used as a potential diagnostic marker for LUAD [14].

Figure 1. (A) Multigene view of lung adenocarcinoma Heat Maps Comparison of all Genes in the study of Hou lung [50]. The expression of KIAA0101 in lung adenocarcinoma was higher than that in the normal control group. (B) Summary view of KIAA0101. The transcription level of KIAA0101 in different types of cancer. Parameter setting: gene: KIAA0101, threshold (P-value): 0.001, threshold (fold change):2, threshold (gene rank): 10%, data type: DNA and mRNA. Note: The color is standardized by the Z-score to describe the relative value in the row. They cannot be used to compare values between rows. Among them, Red signifies gene overexpression or copy gain in the analyses represented by that cell in the table; blue represents the gene's underexpression or copy loss in those analyses. Datasets comprised samples represented as microarray data measuring either mRNA expression on primary tumors, cell lines, or xenografts. (C) Transcription of KIAA0101 in lung adenocarcinoma (from Oncomine, GEPIA, and Ualcan). mRNA expression levels of KIAA0101 were significantly higher in lung adenocarcinoma than in normal tissue. (C1–C6) Shown are the fold change, associated p-values, and overexpression Gene Rank, based on Oncomine 4.5 analysis. Box plot showing KIAA0101 mRNA levels in, respectively, the Hou Lung, Su Lung, Landi Lung, Beer Lung, Selamat Lung and Okayama Lung datasets [50]. (C7) Expression of KIAA0101 in LUAD based on GEPIA analysis; the p-value was 0.0012. (C8) Shows the expression of KIAA0101 in LUAD based on Ualcan analysis; the p-value was 1.62E-12.

KIAA0101 mRNA levels predict prognosis in patients with lung adenocarcinoma

Our next analysis showed that the expression of KIAA0101 had a significant effect on the prognosis of LUAD (Table 1). Figure 2A1–2A6 show the overall survival curve of five datasets (Jacob-00182-CANDF, MICHIGAN-LC, Jacob-00182-MSK, GSE13213, GSE31210) and the relapse free survival curve of GSE31210 datasets. (Figure 2A1–2A6) show six survival curves representing the five different data sets in Table 1 (from the PrognoScan[15] database). We could observe the blue curves (low expression) were higher than the red curves (high expression) in the Kaplan-Meier plots (Figure 2A1–2A6). In addition, we could see from Table 1 that all six Hazard Ratios (HR) were greater than 1.4, the HR [95% confidence interval (CI)-low CI-up] range was greater than one. The Cox p-values were less than 0.05, indicating statistical significance. The results showed that low expression of KIAA0101 was associated with a good prognosis in patients with LUAD. Figure 2B1–2B6 show the overall survival curves of patients using data from the GEPIA [16], LinkedOmics [17], Ualcan [14], TISIDB [18], OncoLnc [19], and TCGA portal [20] databases. We found that patients with LUAD with low KIAA0101 expression had a better prognosis than those with high KIAA0101 expression in six the overall survival (OS) curves (P-value < 0.01). Figure 2C1 and 2C2 show the disease free survival curves (DFS) of patients using data from the GEPIA database. Figure 2D1 and 2D2 show the progression free survival curves (PFS) of patients using data from Kaplan Meier-plotter. We found that patients with LUAD with low KIAA0101 expression had a better prognosis than those with high KIAA0101 expression in four survival curves (P-value < 0.01). These curves reflect the fact that high expression of KIAA0101 is associated negatively with the prognosis of patients with LUAD.

Figure 2. Overall survival curves, progression-free survival curves and disease-free survival curves of KIAA0101 in lung adenocarcinoma. The blue curves represent patients with lung adenocarcinoma with low expression of KIAA0101, and the red curves represent patients with lung adenocarcinoma with high expression of KIAA0101. (A1–A6) Six survival curves representing the six different data sets in Table 1 (from PrognoScan databases), respectively. (B1–B6) The six overall survival curves from the GEPIA, Linkedmics, Ualcan, TISIDB, Oncolnc, and TCGA portal databases, respectively. (C1–C2) Disease free survival curves (DFS) of KIAA0101 from the GEPIA database. (D1–D2) Progression free survival curves (PFS) of KIAA0101 from Kaplan Meier-plotter.

Table 1. Survival analysis of KIAA0101 mRNA in lung adenocarcinoma patients (From PrognoScan).

	DATASET	PROBE ID	ENDPOINT	Number	Ln (HR high/HR low)	COXP-VALUE	Ln (HR)	HR [95% CI-low CI-up]
A1	Jacob-00182-CANDF	202503_s_at	Overall Survival	82	1.03	0.037184	0.57	1.76 [1.03 - 2.99]
A2	MICHIGAN-LC	D14657_at	Overall Survival	86	0.96	0.044546	0.43	1.54 [1.01 - 2.35]
A3	Jacob-00182-MSK	202503_s_at	Overall Survival	104	1.12	0.001309	0.7	2.01 [1.31 - 3.07]
A4	GSE13213	A_23_P117852	Overall Survival	117	1.24	0.004089	0.36	1.44 [1.12 - 1.84]
A5	GSE31210	202503_s_at	Overall Survival	204	1.93	0.000001	1.29	3.65 [2.16 - 6.17]
A6	GSE31210	202503_s_at	Relapse Free Survival	204	1.5	0	1	2.73 [1.90 - 3.91]

Gene set enrichment analysis of KIAA0101 functional networks

Gene set enrichment analysis (GSEA) of KIAA0101 functional networks

(using LinkedOmics [17]). Table 2 shows the top five most significant of the seven GSEA results. All the results were statistically significant; the normalized enrichment scores (NES) were all greater than one; the P-values were all less than 0.05, and the false discovery rates (FDR) were all less than 0.05. Figure 3A shows a bar graph of the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Supplementary Figure 2A–2P display the enrichment plot of pathways in the enrichment results from Figure 3A, with the top 8 and the bottom 8 according to the normalized enrichment score. We observed that the top five pathways of the KEGG [21] enrichment analysis were the cell cycle (Figure 3B), ribosome (Supplementary Figure 3), proteasome (Supplementary Figure 4), spliceosome (Supplementary Figure 5), and DNA replication (Supplementary Figure 6). The gene ontology (GO) results for the gene sets (Cellular Component) included condensed chromosome, chromosomal region, mitochondrial protein complex, ribosome, and spindle. The GO results for the gene sets (Biological Process) included chromosome segregation, DNA replication, cell cycle checkpoint, double-strand break repair, and spindle organization. The GO results for the gene sets (Molecular Function) included structural constituent of ribosome, catalytic activity, acting on DNA, single-stranded DNA binding, helicase activity and catalytic activity, and acting on RNA. Kinase targets included CDK1 (cyclin-dependent kinase 1), PLK1 (polo-like kinase 1), AURKB (aurora kinase B), CDK2 (cyclin-dependent kinase 2), and ATR (ATR serine/threonine kinase). MicroRNA targets included MIR-484, MIR-512-3P, MIR-19A, MIR-19B, MIR-219, and MIR-326. Transcription factor targets included E2F Q6, E2F Q4, E2F4DP1 01, E2F1 Q6, and E2F 02. Supplementary Tables 2–8 show the details of all Leading Edge Genes specifically contained in each gene set.

Figure 3. Gene set enrichment analysis of the KIAA0101 via the KEGG pathway. (A) Bar chart for gene set enrichment analysis of the KIAA0101 via the KEGG pathway. (B) KEGG pathway annotations of the cell cycle pathway (hsa04110). Red denotes leading edge genes; green denotes the remaining genes.

Table 2. Gene Ontology (GO) (Cellular Component), GO (Biological Process), GO (Molecular Function), Kyoto Encyclopedia of Genes and Genomes (KEGG pathway), Kinase, miRNA, and transcription factor-target networks of KIAA0101 in lung adenocarcinoma (LinkedOmics).

Enriched Category	Geneset	LeadingEdgeNum	NES	P Value	FDR
GO (Cellular Component)	condensed chromosome	66	2.6425	0	0
	chromosomal region	94	2.5825	0	0
	mitochondrial protein complex	152	2.3976	0	0
	ribosome	143	2.3858	0	0
	spindle	70	2.3837	0	0
GO (Biological_Process)	chromosome segregation	97	2.6361	0	0
	DNA replication	96	2.4830	0	0
	cell cycle checkpoint	60	2.3720	0	0
	double-strand break repair	61	2.3053	0	0
	spindle organization	44	2.2998	0	0
GO (Molecular_Function)	structural constituent of ribosome	109	2.3582	0	0
	catalytic activity, acting on DNA	69	2.2380	0	0
	single-stranded DNA binding	43	2.1594	0	0
	helicase activity	43	2.0895	0	0
	catalytic activity, acting on RNA	122	2.0460	0	0
KEGG pathway	Cell cycle	48	2.4639	0	0
	Ribosome	100	2.2904	0	0
	Proteasome	40	2.2761	0	0
	Spliceosome	63	2.2601	0	0
	DNA replication	27	2.1887	0	0
Kinase Target	Kinase_CDK1	74	2.3361	0	0
	Kinase_PLK1	32	2.3154	0	0
	Kinase_AURKB	35	2.1660	0	0
	Kinase_CDK2	73	2.1657	0	0
	Kinase_ATR	20	2.0601	0	0
miRNA Target	GAGCCTG,MIR-484	40	-(1.7728	0	0.025589
	CAGCACT,MIR-512-3P	53	(1.6953	0	0.029684
	TTTGCAC,MIR-19A,MIR-19B	148	(1.7059	0	0.034546
	GACAATC,MIR-219	60	(1.7191	0	0.039237
	CCCAGAG,MIR-326	58	(1.6503	0	0.039481
Transcription Factor Target	V$E2F_Q6	87	2.2583	0	0
	V$E2F_Q4	86	2.2538	0	0
	V$E2F4DP1_01	94	2.2226	0	0
	V$E2F1_Q6	96	2.2207	0	0
	V$E2F_02	93	2.1958	0	0
Abbreviations: Leading EdgeNum, the number of leading edge genes; FDR, false discovery rate from Benjamini and Hochberg from gene set enrichment analysis (GSEA); NES, Normalized Enrichment Score. It is generally considered that the absolute value of NES ≥ 1.0, NOM p-val ≤ 0.05, FDR q-val ≤ 0.25 are significant gene sets. The annotation was found in the Molecular Signatures Database (MSigDB) for transcription factors (TF).

Pearson correlated genes, miRNAs and lncRNAs of KIAA0101

The differentially expressed genes correlate highly with KIAA0101 in lung adenocarcinoma (LinkedOmics)

Figure 4A shows a Volcano plot of the results of the Pearson correlation test of KIAA0101 in LUAD. The red and green dots in Figure 4A represent the differentially expressed genes associated with KIAA0101. Figure 4B and 4C show heat maps of the top 50 genes with strong positive and negative correlations with KIAA0101 in LUAD. Figure 4D and 4E show the network views summarizing the predicted association network of proteins strongly related to KIAA0101. Supplementary Figure 7A–7P show scatter diagrams of KIAA0101 and the first 16 genes that are highly related to KIAA0101. From these figures, we observed that the P-value was less than 1E-118; the FDR (BH) was less than 1E-113; and the Pearson correlation coefficient was > 0.8 (Figure 7A–7H), the Pearson correlation coefficient was <-0.6 (Figure 7I–7P). All the genes in the map had a strong positive correlation with KIAA0101.

Figure 4. KIAA0101 highly correlated genes. (A) Pearson test was used to analyze the correlation between KIAA0101 and differentially expressed genes in LUAD. (B, C) Heat maps showing the genes that correlated positively and negatively with KIAA0101 in LUAD (top 50). Red indicates positively correlated genes, green indicates negatively correlated genes. (D, E) The network view summarizes the predicted association network of proteins that are strongly related to the protein product of KIAA0101. Network nodes are proteins. The edge represents the functional association of the prediction. A red line indicates the existence of fusion evidence, a green line represents neighborhood evidence, a blue line represents co-occurrence evidence, a purple line represents experimental evidence, a yellow line represents text mining evidence, and a light blue line represents database evidence.

miRNAs associated with KIAA0101 in patients with LUAD and their prognostic significance

We performed an miRNA Pearson correlation test and a COXPH test of KIAA0101 (Figure 5). From the Volcano plot of KIAA0101-related miRNAs (Figure 5A), we found that the miRNAs hsa-mir-421, hsa-mir-133a-1, hsa-mir-128-2, hsa-mir-101-2, and hsa-mir-664 correlated strongly with KIAA0101. We identified the positive and negative miRNAs of KIAA0101 in LUAD (top 50) from the miRNA heat plots of KIAA0101 (Figure 5B, 5C). Supplementary Figure 8 shows the scatter plots of positive (Supplementary Figure 8A1–8A10) and negative (Supplementary Figure 8B1–8B10) correlations between the expression of KIAA0101 and miRNAs. Their P-values were less than 1E-14, and their FDRs (BH) were less than 1E -12, thus the results were statistically significant. We constructed a Volcano plot of KIAA0101 correlated miRNAs with significance for patient survival in lung adenocarcinoma (Figure 5D). One hundred miRNAs that correlated positively and negatively with the prognosis of patients with LUAD were identified from Figure 5E and 5F. Figure 5G1–5G12 show the KIAA0101-related miRNAs with low expression that were associated with good prognosis. Figure 5G13–5G18 show the KIAA0101-related miRNAs with high expression that were associated with good prognosis. The P values were less than 0.001 and the COXPH hazard ratios were greater than one, indicating that the results were statistically significant.

Figure 5. KIAA0101 highly correlated miRNAs. (A) Volcano plot of KIAA0101 related miRNAs; (B, C) positively and negatively correlated significant miRNA heat plots of KIAA0101. (D) The miRNA volcano map related to the overall survival of LUAD; (E, F) miRNAs positively and negatively related to the overall survival of LUAD, respectively; (G1–G18) the survival curves of KIAA0101 related miRNAs; green represents low expression of the corresponding miRNA, while red represents high expression of the corresponding miRNA.

Long noncoding RNAs (lncRNAs) that correlated with KIAA0101 and were significant for patient survival

Figure 6 shows scatter plots of the lncRNAs that correlated positively (Figure 6A1–6A8) and negatively (Figure 6B1–6B8) with KIAA0101 expression. The results were statistically significant. Figure 6C1–6C8 show the OS curves of lncRNAs related to KIAA0101 expression, in which the Cox P-value of all lncRNAs were less than or equal to 0.001 and the log-rank P-value of all lncRNAs were less than or equal to 0.002. Figure 6C1–6C8 show the KIAA0101-related lncRNAs with low expression that were associated with better prognosis of patients with LUAD. Figure 6D1–6D8 show the KIAA0101-related lncRNAs with low expression that were associated with better prognosis of patients with LUAD.

Figure 6. KIAA0101 highly correlated lncRNAs. (A1–A8) Scatter plots of eight kinds of lncRNAs that correlated positively with KIAA0101 expression. (B1–B8) Scatter plots of eight kinds of lncRNAs that correlated negatively with KIAA0101 expression. (C1–C8) Survival curves of eight kinds of lncRNAs; patients with low expression of lncRNAs have a higher survival rate. (D1–D8) Survival curves of eight kinds of lncRNAs; patients with high expression of lncRNAs have a higher survival rate.

The relationship between immune infiltration and the expression of KIAA0101 in lung adenocarcinoma

Figure 7A–7F show heat maps of the correlation between the expression of KIAA0101 in multiple cancers and different tumor infiltrating lymphocytes (TILs), immunoinhibitors, immunostimulators, MHC molecules, chemokines, and receptors. Figure 7G1–7G18 show scatter diagrams of tumor infiltrating lymphocytes that correlated negatively with KIAA0101 expression in LUAD. Figure 7H1–7H10 show scatter diagrams of TILs that correlated positively with KIAA0101 expression in LUAD. When the expression of KIAA0101 increased, the number of activated CD4 T cells increased. The numbers of Th1 cell, Th17 cells, and follicular helper cell were negatively related to the expression of KIAA0101, and Th2 cell numbers were positively related to the expression of KIAA0101 (P < 0.05). KIAA0101 expression correlated positively with the numbers of effector memory CD8 T cells, natural killer cells, regulatory T cells, activated B cells, immature B cells, plasmacytoid dendritic cells, macrophages, eosinophil, mast cells, and neutrophils (all P < 0.05). Supplementary Figures 9–13 show scatter plots of KIAA0101 expression related to immunoinhibitors, immunostimulators, MHC molecules, chemokines, and chemokine receptors, respectively. Most chemokine receptors correlated negatively with the expression of KIAA0101 (Supplementary Figure 13). The majority of MHC molecules correlated negatively with the expression of KIAA0101 (Supplementary Figure 11).

Figure 7. The relationship between immune infiltration and expression of KIAA0101 in lung adenocarcinoma. (A–F) Heat maps of KIAA0101 expression and lymphocytes, immunoinhibitors, immunostimulators, MHC molecules, chemokines, and receptors in different cancers. (G1–G18) are scatter plots of the negative correlation between KIAA0101 expression and lymphocytes in the treatment of lung adenocarcinoma. (H1–H10) are scatter plots of the positive correlation between KIAA0101 expression and lymphocytes in the treatment of lung adenocarcinoma.

We found that the metabolism of seven drugs upregulated the expression of KIAA0101 (Table 3). They included Acetaminophen [22], Estradiol [23], Genistein [23], Progesterone [24], Resveratrol [25], Rifampicin [26], and Valproic acid [27]. The metabolism of 24 drugs downregulated the expression of KIAA0101. They included amoxicifene, estradiol, yolk, copper, and cyclosporine (Table 3). The metabolism of Estradiol [23, 28], Genistein [23, 29], and Progesterone [24, 30] could both upregulate and downregulate the expression of KIAA0101 (Table 3).

Table 3. The Pharmaco-transcriptomics of KIAA0101 (Up or downregulation of genes caused by the metabolism of pharmaceutical compounds).

DRUG	CHANGE	INTERACTION	REFERENCES (PMID)
Acetaminophen	upregulated	Acetaminophen results in increased expression of KIAA0101 mRNA	25704631
Afimoxifene	downregulated	Afimoxifene results in decreased expression of KIAA0101 mRNA	16514628
Estradiol	downregulated	Estradiol results in decreased expression of KIAA0101 mRNA	23019147
Estradiol	upregulated	Estradiol results in increased expression of KIAA0101 mRNA	16474171
Custirsen	downregulated	CC-8490 results in decreased expression of KIAA0101 mRNA	15604281
Copper	downregulated	Binding with copper resulted in decreased expression of KIAA0101 mRNA	20971185
Cyclosporine	downregulated	Cyclosporine results in decreased expression of KIAA0101 mRNA	20106945
Dasatinib	downregulated	Dasatinib results in decreased expression of KIAA0101 mRNA	20579391
Dronabinol	downregulated	Dronabinol results in decreased expression of KIAA0101 mRNA	18454173
Calcitriol	downregulated	Calcitriol results in decreased expression of KIAA0101 mRNA	21592394
Fluorouracil	downregulated	Fluorouracil results in decreased expression of KIAA0101 mRNA	17039268
Fulvestrant	downregulated	fulvestrant results in decreased expression of KIAA0101 mRNA	16514628
Genistein	downregulated	Genistein results in decreased expression of KIAA0101 mRNA	19371625
Genistein	upregulated	Genistein results in increased expression of KIAA0101 mRNA	16474171
Lucanthone	downregulated	Lucanthone results in decreased expression of KIAA0101 mRNA	21148553
Metamfetamine	downregulated	Methamphetamine results in decreased expression of KIAA0101 mRNA	25290377
Methotrexate	downregulated	Methotrexate results in decreased expression of KIAA0101 mRNA	24657277
Palbociclib	downregulated	Palbociclib results in decreased expression of KIAA0101 mRNA	22869556
Phenethyl Isothiocyanate	downregulated	Phenethyl isothiocyanate results in decreased expression of KIAA0101 mRNA	26678675
Piroxicam	downregulated	Piroxicam results in decreased expression of KIAA0101 mRNA	21858171
Progesterone	downregulated	Progesterone results in decreased expression of KIAA0101 mRNA	21795739
Progesterone	upregulated	Progesterone results in increased expression of KIAA0101 mRNA	18070364
Raloxifene	downregulated	Raloxifene Hydrochloride results in decreased expression of KIAA0101 mRNA	16514628
Resveratrol	upregulated	Resveratrol results in increased expression of KIAA0101 mRNA	19167446
Rifampicin	upregulated	Rifampin results in increased expression of KIAA0101 mRNA	24552687
Silicon dioxide	downregulated	Silicon Dioxide analog results in decreased expression of KIAA0101 mRNA	25895662
Tamoxifen	downregulated	Tamoxifen results in decreased expression of KIAA0101 mRNA	15604281
Testosterone	downregulated	Testosterone results in decreased expression of KIAA0101 mRNA	21592394
Valproic acid	upregulated	Valproic Acid results in increased expression of KIAA0101 mRNA	23179753
Vitamin E	downregulated	Vitamin E results in decreased expression of KIAA0101 mRNA	19244175
Zoledronic acid	downregulated	Zoledronic acid results in decreased expression of KIAA0101 mRNA	24714768

Abbreviations

KIAA0101/PCLAF: proliferating cell nuclear antigen binding factor; PCNA: proliferating cell nuclear antigen; LUAD: lung adenocarcinoma; GEO: Gene Expression Omnibus.

Author Contributions

Sheng Hu and Yiping Wei designed and performed the research; analyzed and interpreted the data; and drafted the manuscript. Weibiao Zeng, Wenxiong Zhang, Jianjun Xu, Dongliang Yu and Jinhua Peng conceived the study and participated in the research design and data interpretation. All authors read and approved the final manuscript.

Acknowledgments

We hereby thank the Department of Thoracic Surgery of the Second Affiliated Hospital of Nanchang University for their strong support for this study.

Conflicts of Interest

All the data in this paper are public, and the quoted data have indicated the source. There is no conflicts of interest in this paper.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81560345 and 81860379), the Preeminence Youth Fund of Jiangxi Province (20162BCB23058), the China Postdoctoral Science Foundation Grant (2017M610401), and the Science and Technology Planning Project at the Department of Science and Technology of Jiangxi Province, China (20151BBG70165 and 20171BAB205075).

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