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. 2022 Feb 17:9:820174.
doi: 10.3389/fcell.2021.820174. eCollection 2021.

Systematic Analysis of Molecular Characterization and Clinical Relevance of Liquid-Liquid Phase Separation Regulators in Digestive System Neoplasms

Yaxin Zhang  1 , Jie Li  1 , Dan Feng  1 , Xiaobo Peng  1 , Bin Wang  1 , Ting Han  2 , Yingyi Zhang  1
Affiliations

Systematic Analysis of Molecular Characterization and Clinical Relevance of Liquid-Liquid Phase Separation Regulators in Digestive System Neoplasms

Yaxin Zhang et al. Front Cell Dev Biol. .

Abstract

Background: The role of liquid-liquid phase separation (LLPS) in cancer has also attracted more and more attention, which is found to affect transcriptional regulation, maintaining genomic stability and signal transduction, and contribute to the occurrence and progression of tumors. However, the role of LLPS in digestive system tumors is still largely unknown. Results: Here, we characterized the expression profiles of LLPS regulators in 3 digestive tract tumor types such as COAD, STAD, and ESCA with The Cancer Genome Atlas (TCGA) data. Our results for the first time showed that LLPS regulatory factors, such as Brd4, FBN1, and TP53, were frequently mutated in all types of digestive system tumors. Variant allele frequency (VAF) and APOBEC analysis demonstrated that genetic alterations of LLPS regulators were related to the progression of digestive system neoplasms (DSNs), such as TP53, NPHS1, TNRC6B, ITSN1, TNPO1, PML, AR, BRD4, DLG4, and PTPN1. KM plotter analysis showed that the mutation status of LLPS regulators was significantly related to the overall survival (OS) time of DSNs, indicating that they may contribute to the progression of DSN. The expression analysis of LLPS regulatory factors showed that a variety of LLPS regulatory factors were significantly dysregulated in digestive system tumors, such as SYN2 and MAPT. It is worth noting that we first found that LLPS regulatory factors were significantly correlated with tumor immune infiltration of B cells, CD4+ T cells, and CD8+ T cells in digestive system tumors. Bioinformatics analysis showed that the LLPS regulators' expression was closely related to multiple signaling, including the ErbB signaling pathway and T-cell receptor signaling pathway. Finally, several LLPS signatures were constructed and had a strong prognostic stratification ability in different digestive gland tumors. Finally, the results demonstrated the LLPS regulators' signature score was significantly positively related to the infiltration levels of CD4+ T cells, neutrophil cells, macrophage cells, and CD8+ T cells. Conclusion: Our study for the first time showed the potential roles of LLPS regulators in carcinogenesis and provide novel insights to identify novel biomarkers for the prediction of immune therapy and prognosis of DSNs.

Keywords: TCGA; cancers; liquid-liquid phase separation regulators; prognosis; tumor immune infiltration.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Genetic alterations of LLPS regulators in digestive system neoplasms. (A) The Top LLPS gene alteration of LLPS in COAD. (B) The LLPS gene co-occurrence and mutual exclusion analysis in COAD. (C) The Top LLPS gene alteration of LLPS in STAD. (D) The LLPS gene co-occurrence and mutual exclusion analysis in STAD. (E) The Top LLPS gene alteration of LLPS in ESCA. (F) The LLPS gene co-occurrence and mutual exclusion analysis in ESCA.
FIGURE 2
FIGURE 2
Genetic alterations of LLPS regulators were related to the progression of digestive system neoplasms. (A,C,E) The APOBEC-signature mutation load of LLPS gene in COAD (A), STAD (C), and ESCA (E). (B,D,F) The VAF analysis of LLPS gene in COAD (B), STAD (D), and ESCA (F).
FIGURE 3
FIGURE 3
Genetic alterations of LLPS regulators were related to the prognosis of digestive system neoplasms. (A–C) The enrichment of LLPS gene mutation in different type of pathologic M in COAD (A), in different type of pathologic T in STAD (B), and in different disease type of ESCA (C). (D) The Cox regression of LLPS gene mutation corresponding to the OS in COAD. (E) The LLPS gene mutation signature indicated the good prognosis in COAD. (F) The landscape of LLPS gene mutation signature in COAD. (G) The Cox regression of LLPS gene mutation corresponding to the OS in COAD. (H) The LLPS gene mutation signature indicated the good prognosis in COAD. (I) The landscape of LLPS gene mutation signature in COAD.
FIGURE 4
FIGURE 4
Predicting the drug response in digestive system neoplasms based on genetic alterations of LLPS regulators. (A–C) We predicted the drug response in COAD (A), STAD (B), and ESCA (C) patients based on genetic alterations of LLPS regulators.
FIGURE 5
FIGURE 5
LLPS regulators were significantly differently expressed in digestive system neoplasms. (A) The heatmap and cluster analysis of the LLPS gene expression in the digestive tract tumors. (B) The volcano plot for differential LLPS gene in the digestive tract tumors. (C) The Venn diagram of the differential LLPS among the digestive tract tumors. (D) The Boxplot of the low expression LLPS gene in all digestive tract tumors.
FIGURE 6
FIGURE 6
LLPS regulators were significantly related to tumor immune infiltration in digestive system neoplasms. (A–D) The correlation of LLPS gene expression with percentage of immune cell predicated by CIBERSORT.
FIGURE 7
FIGURE 7
Construction of LLPS regulators signature in digestive system neoplasms. (A–C) LASSO regression identified the most significant prognosis-related genes in CRC (A), ESCA (B), and STAD (C). (D–F) Our results showed that the OS was remarkedly shorter in the high-risk group than that in the low-risk group in CRC (D), ESCA (E), and STAD (F). (G–I) Time-dependent ROC analysis of established score in CRC (G), ESCA (H), and STAD (I).
FIGURE 8
FIGURE 8
The levels of LLPS regulators’ signature associated with immune infiltration. (A–C) The LLPS regulators’ signature score was related to the levels of B cells, CD4+ T-cell infiltration, CD8+ T-cell infiltration, neutrophil cell infiltration, macrophage infiltration, and myeloid dendritic cell infiltration in COAD (A), STAD (B), and ESCA (C).
FIGURE 9
FIGURE 9
Comprehensively Bioinformatic analysis of LLPS regulators in digestive system neoplasms. (A–B) KEGG analysis of differently expressed LLPS regulators in COAD (A) and ESCA (B). (C) GO analysis of LLPS regulators in COAD, STAD, READ, and ESCA.
FIGURE 10
FIGURE 10
Construction of LLPS regulators–signaling network in digestive system neoplasms. (A–B) Construction of LLPS regulators–KEGG signaling network in COAD (A) and ESCA (B). (C) Construction of LLPS regulators–biological processes in COAD, STAD, READ, and ESCA.
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