Hippo signaling pathway is a highly conserved intracellular communication network in multiple species. It was originally discovered from Hippo kinase in Drosophila and mainly comprises the upstream activated factors, such as FAT4 and DACHS; core kinase molecules, such as MST1/2 and LATS1/2; and co-transcription factors including YAP and transcriptional co-activator with PDZ-binding motif (TAZ) (1, 2). When Hippo signaling is inhibited, TAZ is translocated to the nucleus from the cytoplasm and acts as a co-transcription factor with other transcription factors such as TEADs, RUNXs to form transcription complexes, thereby regulating the transcriptional expression of a series of downstream target genes (e.g., TEADs, Runxs) (3, 4). Recent studies have reported that the activation of TAZ is closely linked with tumorigenesis as it regulates a series of malignant biological behaviors, such as malignant proliferation, invasion, metastasis, and chemotherapy resistance (5–8).

The Hippo effector TAZ is short for “TAZ.” It is encoded by the WWTR1 gene and located at 3q25 in humans (9). In recent years, TAZ has been identified as an oncogene in several tumor types such as breast, lung, prostate, and ovarian cancers (5–8). Maugeri-Sacca et al. (10) have demonstrated that the high expression of TAZ is associated with the promotion of epithelial-mesenchymal transition (EMT) and chemotherapy resistance in breast cancer. Furthermore, the activation of TAZ is also connected to various cancer hallmarks, such as EMT in thyroid carcinoma (11), glutamine metabolism in breast cancer (12), and chemotherapy resistance in non-small-cell lung cancer (13). Moreover, the expression of TAZ holds prospective prognosis value in certain tumor types. Van Haele et al. (14) have established that the nuclear expression of TAZ is an independent predictor of poor recurrence-free survival (RFS) and overall survival (OS) in hepatocellular carcinoma patients. In colorectal cancer (CRC), several previous studies have reported the association of TAZ with prognosis and tumor aggressiveness (15–17). Moreover, recent studies demonstrated that Hippo pathway was associated with the tumor immunity (18, 19). TAZ may be served as a signal hub that link the cancer cells and immune cells, which can influence the formation of tumor microenvironment (TME), thereby promoting the immune escape (20, 21). However, the specific function and immune role of TAZ in CRC has not been fully elucidated.

Accordingly, in this study, we investigated the expression of TAZ in CRC and matched normal tissues for analyzing the correlation between TAZ expression and clinicopathological characteristics in CRC. Furthermore, we analyzed the role of TAZ in the CRC-associated immunology using an integrative bioinformatic analyses. Thus, the aim of this study was to assess the clinical significance and potential role of TAZ, and to analyze the relationship between TAZ expression and immune infiltration in CRC.

Colorectal cancer is the third most commonly diagnosed malignant tumor in the world (40, 41), exhibiting high risk of recurrence and distant metastasis. Despite the ever-advancing novel strategies for CRC prevention and treatment (42), the 5-year relative survival rate of postmetastatic CRC is less than 15% (43, 44). Therefore, the pathological mechanisms that promote the tumorigenesis of CRC must be investigated to provide potential targets for effective clinical diagnosis and treatment. As a key downstream effector of Hippo pathway, TAZ has been recently identified as an oncogene in certain tumor types. Moreover, the aberrant expression of TAZ has been identified to be associated with the development of breast, liver, and thyroid cancers (10, 11, 14). Wang et al. (45) have studied the combined amplification of TAZ gene in 33 cancer cell types and found that TAZ exhibits the most significant amplification rate in five common types of squamous cell carcinomas including cervical squamous cell carcinoma (CESC), LUSC, ESCA, HNSC, and BLCA. Furthermore, this study demonstrated that the frequent amplification of YAP1 and TAZ occurred in a mutually exclusive manner in HNSC and CESC, in addition to delineating the molecular mechanism of TAZ being involved in the regulation of squamous cell carcinoma progression. However, the roles and the mechanisms involving TAZ in CRC progression have rarely been investigated. Accordingly, in this study, we performed the integrative bioinformatic analyses of the expression level of TAZ in CRC employing the publicly available cancer gene expression databases. Our results revealed that the mRNA and protein expressions of TAZ were significantly overexpressed in CRC compared to those in the matched normal adjacent tissues. Furthermore, our analysis showed that high TAZ expression was significantly associated with the N stage and degree of differentiation in CRC. Likewise, CRC patients with high TAZ expression levels were also identified to exhibit lower OS and RFS than those with low TAZ expression. Moreover, we found that patients with high TAZ expression levels had lower OS and RFS by the Kaplan-Meier analysis. However, Wang et al. (16) reported that patients with high YAP expression levels had poor prognosis in CRC, especially when TAZ was co-expressed, but at multivariate analysis TAZ alone showed no statistical correlation to prognosis. Because the small sample size limits, this study was not entirely concluded that YAP is a better biomarker or the YAP + TAZ is the best biomarker. Furthermore, Mouillet-Richard et al. (35) found that TAZ mRNA is clearly enriched in CMS4 tumors by the examination of the levels of TAZ by CMS classification, those tumors known to express EMT, TGF-b, and have a worse survival; while, TAZ has a low expression in CMS2 and CMS3 type of tumors. Interestingly, immune infiltration is related to a better outcome in CRC as examined by “immunoscore,” and CMS4 microenvironment is rich in “immune suppressors” (46). In a word, these results indicated the potential of TAZ to become a biomarker in CRC.

The gene co-expression analysis is a high throughput correlation analysis which distinctly illustrates the molecular interaction and systematically corresponds the targeted gene functions with specific biological process. Currently, the gene co-expression network has become a crucial method to search for novel gene markers for CRC targeted therapy (47, 48). In this study, we used the cBioPortal database to analyze the co-expression network of TAZ and finally found out three genes which had the highest correlation: CXCR4, CXCL12 and Secreted Phosphoprotein 1 (SPP1). These three molecules are closely related to the tumor immune response. For example, Yu et al. (49) also demonstrated that CXCL12/CXCR4 is involved in the regulation of CRC proliferation. CXCL12/CXCR4 can sponge miR-133-a-3p and liberate its inhibitory effect on RhoA pathways, thus inducing the cytoskeletal remodeling and immunocytes recruitment, and promoting the progression of inflammatory CRC. Moreover, Zhang et al. (50) reported that SPP1 overexpression can positively regulate the expression of PD-L1, thereby promoting the macrophage polarization and immune escape in lung cancer. Interestingly, targeting the CXCR4, CXCL12, and SPP1 for CRC chemotherapy have been reported. For example, Jung et al. (51) demonstrated that bevacizumab and ramucirumab combined with the inhibitors AMD3100 of CXCR4 can improve the blockade in CRC angiogenesis. Cutler et al. (52) found that the chemotherapy drug 5-fluorouracil might inhibit tumor migration by selecting for CXCR4-negative cells in CRC. Moreover, SPP1 has been demonstrated to be significantly overexpressed in afatinib-resistant lung cancer cells, and that the knockdown of SPP1 increases the chemotherapy sensitivity of lung cancer cells. These findings thus indicate that SPP1 can serve as a potential target for overcoming afatinib resistance (53). Consequently, we firmly believe that further studies on the correlation between TAZ and these co-expressed genes has the potential to provide new immunotherapy targets for CRC.

Interestingly, our KEGG analysis results revealed the correlation between TAZ expression and TGF-β signaling pathway, which has been reported to regulate extracellular matrix production, tissue fibrosis, and inflammation (54). Furthermore, the TGF-β signaling pathway is associated with the tumorigenesis, including EMT, immune escape and tumor angiogenesis (55). Li et al. (56) revealed that TAZ was involved in TGF-β1-induced EMT in oral cancer cells. Pseftogas et al. (57) explored the regulatory effect of CYLD in the hyperplastic alterations in the mammary epithelium of breast cancer, which is associated with the increased nuclear expression of TAZ and phosphorylation of Smad2/3, a key factor in TGF-β pathway, further supporting the involvement of TAZ in TGF-β-facilitated tumorigenesis. In view of the strong influence of TGF-β pathway on the formation of TME and tumor immune infiltration (58), the crosstalk between TAZ and TGF-β pathway may become a fresh entry point for targeted drug research. The correlation with “cytokine-cytokine receptor interaction” also indicates the potential mechanism of TAZ on the regulation of tumor immune landscape. Many cytokines such as interleukin play important roles in tumor immune process. IL-17 was reported to inhibit T cell attracting chemokines CXCL9 and CXCL10, thereby inhibiting the recruitment of CD8⁺ T cells and Treg cells in CRC, which helped the immune escape of tumor cells (59). Matsushita et al. (60) found that activated TAZ most significantly enhanced the transcription of genes related to “cytokine-cytokine receptor interaction” in malignant mesothelioma (MM). Their studies revealed that IL-1β induced by TAZ was a key factor for the development of malignant phenotype of mesothelioma cells.

Tumor immunotherapy has been widely investigated and employed in clinical fields, as it holds great promise as a neoadjuvant therapy besides surgery and radiotherapy (61–63). At present, many inhibitors have been identified to play emerging roles in tumor suppression by regulating TME or assisting immuno-surveillance by immune cells (64). Hippo pathway has is involved in the regulation of immune processes associated with tumorigenesis. Geng et al. (65) have shown that TAZ is a key co-activator of the Th17 transcription factor Rorγt, which is responsible for the differentiation of precursor CD4⁺ T cells into inflammatory Th17 cells. In contrast, TAZ has also been reported to suppress the acetylation of Foxp3 and inhibit the generation of Treg cells, suggesting that TAZ plays an important role in the lineage balance of Th17/Treg cells. SKIL is an important oncogene that regulates the induction of TGF-β pathway (66). Furthermore, Ma et al. (67) have reported that SKIL facilitates the immune escape of non-small cell lung cancer (NSCLC) cells by enhancing the expression of TAZ and activating the STRING pathway to induce the autophagy of malignant cells. In our study, we have determined that TAZ expression has significant correlation with the infiltration of CD4⁺ T, CD8⁺ T, and B cells in CRC using the TIMER database. Remarkably, our results demonstrate statistically significant correlation of TAZ expression with the expression CD8⁺ T cells, B cells, other T cells, macrophages, neutrophils, and monocyte gene markers. However, the specific mechanism illustrating the involvement of TAZ in regulating the tumor-associated immunological processes lacks evidence, and the effects of prospective application of TAZ-related inhibitors on CRC immunotherapy remain to be further explored.

In summary, our study provides comprehensive evidence that overexpression of TAZ in CRC tissues was highly correlated with the carcinogenesis and poor prognosis of CRC. Moreover, our co-expressed gene network and functional analysis indicated a notable correlation between TAZ expression and tumor metabolism as well as inflammation. Likewise, the expression of TAZ had a significant correlation with the immune infiltrating levels of CD4⁺ T, CD8⁺ T, and B cells, as well as the expression of immune cell specific gene markers in CRC tissues. Overall, our findings suggest that TAZ will become a novel biomarker in the diagnosis and treatment of CRC.

The original contributions presented in this study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Xiangya Hospital, Central South University. The patients/participants provided their written informed consent to participate in this study.

YW and HN conducted experimental operations, sample processing, data analysis, and performed the experiments. CO conceived and designed the experiments. All authors participated in writing the manuscript, read, and approved the final manuscript.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.