Clinicopathological and prognostic significance of Trophinin-associated protein expression and its relationship with P53 status in pulmonary sarcomatoid carcinoma: A retrospective multicenter study based on bioinformatic analysis

doi:10.21203/rs.3.rs-1349212/v1

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Clinicopathological and prognostic significance of Trophinin-associated protein expression and its relationship with P53 status in pulmonary sarcomatoid carcinoma: A retrospective multicenter study based on bioinformatic analysis

https://doi.org/10.21203/rs.3.rs-1349212/v1

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Trophinin-associated protein (TROAP) levels and P53 status have been used to predict the prognosis of various human tumors. However, the clinicopathological and prognostic significance of TROAP expression and P53 status in pulmonary sarcomatoid carcinoma (PSC) has not yet been elucidated. TROAP gene was selected as candidate by bioinformatics analysis based on TCGA and GEO database. We investigated TROAP and P53 expression in 168 cases of surgically resected PSC in three cancer centers using immunohistochemistry (IHC), and then analyzed the correlation between TROAP expression and various clinicopathological parameters, including P53 status and patient prognosis, using several statistical models. The results showed that lung cancer patients with high TROAP mRNA levels had worse prognosis by TCGA and GEO databases. The significant association between the high expression of TROAP, aberrant P53 expression, and adverse overall survival and disease-free survival (P < 0.05) was identified using univariate analysis. Multivariate analysis showed that TROAP expression in PSC acted as an independent prognostic factor for overall survival (P < 0.05). Risk stratified analysis demonstrated that patients in high risk group had the worst overall survival (P < 0.001) and disease-free survival (P = 0.006) compared with that in the other two groups, based on TROAP expression and P53 status. High TROAP expression might be important in conferring a more aggressive behavior in PSC. Thus, TROAP expression might be regarded as a novel independent prognostic biomarker for patients with PSC and for PSC harboring aberrant P53 expression.

Trophinin-associated protein

TROAP

P53

pulmonary sarcomatoid carcinoma

PSC

prognosis

We investigated TROAP expression and P53 status in PSC
TROAP expression correlates significantly with P53 status, clinical stage, and N stage
High TROAP expression and aberrant P53 expression associate with poor OS and DFS
High TROAP levels might confer a more aggressive behavior in PSC
TROAP expression may be an independent prognostic biomarker for P53-aberrant PSC

Pulmonary sarcomatoid carcinoma (PSC) belongs to a rare subtype of lung cancer that represents less than 1% of all pulmonary malignant tumors [53]. The poorly differentiated nature of PSC is reflected by a heterogeneous group of non-small cell lung cancer (NSCLC) intermingling with a sarcoma or a sarcoma-like component or pure sarcomatoid morphology. They are histologically divided into five subtypes based on their microscopic morphology, including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma, according to 2015 World Health Organization classification of lung tumors [45]. PSCs are aggressive tumors, with a 5-year overall survival rate ranging from 6 to 24.5%, and are characterized by a significantly worse clinical outcome than other NSCLCs, even in the early stage of the disease [8, 31, 47]. Despite the poor long-term survival, the current predominant therapeutic approach for patients with PSC remains surgical resection because of PSC’s resistance to standard platinum-based chemotherapy and its unsatisfactory response to radiotherapy, which is similar to the treatment strategies for other NSCLCs [29, 34, 35, 48]. Advances in the treatment of lung cancer, especially adenocarcinomas, have continued to emerge during recent decades, which is predominantly attributed to the discovery of certain targeted genetic alterations including epidermal growth factor receptor (EGFR)-activating mutations and a fusion protein between the N-terminal portion of the echinoderm microtubule-associated protein-like 4 protein and the intracellular signaling portion of the anaplastic lymphoma kinase tyrosine kinase receptor (EML4ALK). Patients carrying one or two of these genetic abnormalities are sensitive to tyrosine kinase inhibitors (TKIs)[5, 26, 30, 44]. However, a lack of genomic abnormalities and molecular features have hampered the improvement of targeted therapeutic strategies because of the rarity of PSC. In recent years, several studies have focused on the genomic alterations in PSC via stepby step analyses using the Next generation sequencing (NGS)-based approaches, which found the mutations in several oncogenes and tumor-suppressor genes such as those encoding tumor protein P53 (TP53 or just P53), KRAS proto-oncogene, GTPase (KRAS), EGFR, Janus kinase 3 (JAK3), AKT serine/threonine kinase 1(AKT1), ATM serine/threonine kinase (ATM), MET proto-oncogene, receptor tyrosine Kinase (MET), KIT proto-oncogene, receptor tyrosine kinase (KIT), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) as well as the novel mutations of additional genes including those encoding RAS P21 Protein Activator 1 (RASA1), cadherin 4 (CDH4), cadherin 7 (CDH7), laminin subunit beta 4 (LAMB4), SR-related CTD associated factor 1 (SCAF1), and lemur tyrosine kinase 2 (LMTK2) [27–29, 39, 43, 55]. Isolated studies of responses to targeted therapy have been reported [28,55]; however, the efficacy of targeted therapy remain to be investigated. Interestingly, no matter what the conclusions of the above-mentioned studies, high rates of P53 mutation ranging from 57.1 to 74% were identified using an NGS-based approach for PSC. P53 mutations could function as oncogenes related to tumor progression, including cell-cycle progression or cell migration, resulting in malignant transformation and resistance to anticancer therapy [46]. P53 mutations are also an important reason why patients with PSC have a poor clinical outcome. Moreover, to date, although several cancer therapeutic strategies to restore p53 functions in cancers harboring TP53 mutations have been developed [4, 20, 36, 38, 41, 54], the clinical value and efficacy of these therapeutic strategies remain to be investigated because these studies are still at the preliminary exploration stage. Therefore, it is necessary to explore new biomarkers for early diagnosis and to evaluate prognosis, and to seek more effective therapeutic strategies for PSC.

Trophinin-associated protein (TROAP, also called tastin), encoded by the TROAP gene, is a cytoplasmic protein comprising 778 amino acid residues that mediates the initial attachment of the trophoblast to the endometrial epithelium in early embryo implantation, which involves the formation of a complex consisting of trophinin and its associated proteins, TROAP and bystin [11, 13, 50]. The aggressive behavior of trophoblasts in the process of embryo implantation could reflect similar mechanisms that occur in malignant tumor cells [13]. In addition, a recent study reported that TROAP is required for spindle assembly and centrosome integrity during mitosis II and plays a crucial role in cell proliferation. For example, the expression TROAP peaks in the G2/M phase and then suddenly decreases after cell division [24, 50], which process is also associated with the most common P53 signaling pathway. TROAP also promotes proliferation, invasion, and metastasis in breast cancer [25], lung adenocarcinoma [9], liver cancer [17], and prostate cancer [51]. However, no studies have reported the prognostic significance of TROAP in PSC. Therefore, the present study aimed to investigate the expression status of TROAP protein in PSC and the relationship of TROAP and TP53 protein expression using a tissue-microarray and immunohistochemistry (IHC).

Bioinformatic analysis based on online database

UALCAN analysis (http://ualcan.path.uab.edu/analysis) [7], online analysis using iBioSci Tools v5.0 (http://www.chrislifescience.club:3838/R/AnnoE2/), and Gene Expression Profiling Interactive Analysis (GEPIA: http://gepia.cancer-pku.cn/detail.php) based on The Cancer Genome Atlas (TCGA) dataset were used to examine TROAP mRNA expression in RNA-Sequencing data. The TROAP gene was used as a search to query the database and the results were obtained from studies of lung adenocarcinoma with regards to TROAP expression data. We selected lung adenocarcinoma as the objective of the study because PSC has a mutational profile similar to that of lung adenocarcinoma [29]. In addition, GEPIA analysis and the ProggeneV2 prognostic database (http://watson.compbio.iupui.edu/chirayu) was used to analyze survival data associated with TROAP mRNA expression in lung adenocarcinoma for the TCGA and GEO datasets, respectively [14]. The cBioPortal for Cancer Genomics (http://www.cbioportal.org/) was applied to identify the relationship between TROAP mRNA and P53 status, and online analysis using iBioSci Tools v5.0 was used to predict the function of TROAP in the signaling pathways involving P53.

Patients and tissue specimens

In this study, we analyzed retrospective data from 167 specimens of PSC collected in the Sun Yatsen University Cancer Center, Guangdong Provincial People’s Hospital and Ganzhou cancer hospital between December 2000 and June 2016 by removing the patients with neoadjuvant therapy and those who received pneumonectomy and/or lymphadenectomy. All cases were diagnosed according to the WHO classification criteria of the 2000 and 2002 US Joint Commission and the International Joint Cancer TNM Classification System. This study was approved by the Sun Yat-Sen University Cancer Center Medical Ethics Committee.

Immunohistochemistry (IHC)

The immunohistochemical staining of TROAP and P53 was performed according to the standard EnVision™ procedure (Envision, Dako, Denmark). The paraffin-embedded tissue blocks were cut into 3-µm thick sequential sections. The slides were dried and deparaffinized in xylene, rehydrated through graded alcohol, immersed in 3% hydrogen peroxide for 10 min to block endogenous peroxidase activity, and the antigens were retrieved by pressure cooking for 3 min in citrate buffer (pH = 6). Subsequently, the slides were incubated with rabbit polyclonal antibodies recognizing TROAP (Thermo Fisher Scientific, Waltham, MA, USA; catalog # PA5-60613, RRID AB_2648975., dilution 1:500) and -P53 (Abcam, Cambridge, MS, USA; ab32389, dilution 1:100) for 50 min at 37 ℃, separately. The slides were then incubated with a secondary antibody (Envision) for 30 min in the incubator at 37°C, and stained with 3,3-diaminobenzidine (DAB). Finally, the sections were counterstained with Mayer’s hematoxylin, dehydrated, and mounted. A negative control was obtained by replacing the primary antibody with a normal rabbit IgG.

IHC evaluation

The assessment of TROAP expression was performed by two independent pathologists. The number of positively stained tumor cells was defined as a percentage (%), and the intensity of staining was evaluated as ("-", "1+", "2+", "3+"). Finally, each intensity multiplied by the percentage of the corresponding positive cells to obtain the score of each sample. The assessment of P53 expression was also performed by two independent pathologists. According to previous research [6, 40], P53 is regarded as having ‘aberrant expression’ when its shows nuclear expression in greater than 60% of tumor cells or a complete absence of staining in tumor cells. ‘Wild-type expression’ was identified as no aberrant expression (ranging from 1 to 60% staining in tumor cells).

Selection of a cutoff value for TROAP expression

Receiver operating characteristic (ROC) curve analysis was used to identify the cut-off value of TROAP expression [15]. The sensitivity and specificity for each clinicopathological factor was graphically represented to evaluate the status of TROAP expression, which generated the corresponding ROC curves. The ideal value with both maximum sensitivity and specificity was selected as the cutoff value.

Statistical analysis

Statistical analysis was performed using SPSS 16.0 (IBM Corp., Armonk, NY, USA). The correlation between TROAP protein expression and the clinicopathological parameters, including P53 status, in patients with PSC was analyzed using the Chi-squared test. The survival analysis of patients with PSC was evaluated using Kaplan–Meier analysis with the log-rank test. Multivariate analyses were performed using the Cox proportional hazard model. All P values were reported by two-sided analyses and P < 0.05 was accepted as statistically significant.

The results of Bioinformatic analyses based on online databases

The publicly available array data source showed that TROAP mRNA is expressed at higher levels in lung adenocarcinoma than in normal tissues, as evidenced by the heatmap generated using UALCAN analysis and the boxplot generated through GEPIA analysis) (Fig. 1A, C; P < 0.05). Online analysis using iBioSci Tools v5.0 displayed the upregulation of TROAP mRNA expression in lung adenocarcinoma as a volcano plot (Fig. 1B) based on TCGA data. In addition, GEPIA demonstrated that TROAP mRNA expression is higher in stage III–IV lung adenocarcinoma compared with that in stage I–II lung adenocarcinoma (Fig. 1D, P < 0.05). Higher TROAP mRNA expression is significantly associated with shorter overall survival (OS) and disease-free survival (DFS) (Fig. 1E, F; P < 0.05). In addition, by exploring the PROGgeneV2 Prognostic Database of GEO, we found that in the dataset (GSE13213), TROAP mRNA levels that were higher than the median expression level were inversely associated with worse OS compared with those with lower TROAP expression (Fig. 1G, P < 0.05). Notably, patient data in another dataset (GSE31210) showed that higher TROAP mRNA expression was associated with a shorter relapse-free survival (RFS) (Fig. 1H, P < 0.05).

cBioPortal for Cancer Genomics (http://www.cbioportal.org/) identified a significantly negative relationship between TROAP mRNA expression and P53 status (displayed predominantly as mutation or not) (Fig. 2A, P < 0.05). Online analysis using iBioSci Tools v5.0 predicted that the function of TROAP is closely linked to signaling pathways involving P53 (Fig. 2B). GeneMANIA software predicted that p53 and TROAP interacted via Erb-B2 receptor tyrosine kinase 4 (ERBB4) or marker of proliferation Ki-67 (MKI67) (Fig. 2C).

Patients’ characteristics

The clinicopathological feathers of the patients with PSC are described in Table 1. The cohort with PSC consisted of 142 (84.5%) men and 26 (15.5%) women, with a mean age of 57.7 years. Their median survival time was 31.7 months (the follow-up period ranged from 0.3 to 129.0 months) and the 5-year survival rate was approximately 35.0%. Ninety-two (54.8%) patients were diagnosed at late stages (III and IV), and 76 patients (45.2%) were diagnosed at early stages (I and II).

Table 1

Correlation between the clinicopathologic variables and expression of TROAP in **PSC**.
Variable	Expression of TROAP
Variable	All cases	Low expression	High expression	P value ^a
Age (years) ^b				0.062
≤ 57.7	83	45 (54.2%)	38(45.8%)
> 57.7	85	58 (68.2%)	27 (31.8%)
Gender				0.680
Male	142	88 (62.0%)	54 (38.0%)
Female	26	15 (57.7%)	11 (42.3%)
Tumor size ^c				0.146
≤ 4.7	71	39 (54.9%)	32 (45.1%)
> 4.7	97	64 (66.0%)	33 (34.0%)
Smoking				0.752
Yes	57	34 (59.6%)	23 (40.4%)
No	111	69 (62.2%)	42 (37.8%)
T stage				0.187
T1 - T2	101	66 (65.3%)	35 (34.7%)
T3 -T4	67	37 (55.2%)	30 (44.8%)
N stage				< 0.001
N0	86	66 (76.7%)	20 (23.3%)
N1 - N3	82	37 (45.1%)	45 (54.9%)
M stage				0.810
M0	146	89(61.0%)	57(39.0%)
M1	22	14 (63.6%)	8 (36.4%)
Clinical stage				0.003
I-II	76	56 (73.7%)	20 (26.3%)
III-IV	92	47 (51.1%)	45 (48.9%)
Recurrence				0.073
Yes	56	29 (51.8%)	27 (48.2%)
No	112	74 (66.1%)	38 (33.9%)
P53 status				0.033
Aberrant expression	112	75 (67.0%)	37 (33.0%)
Wild type expression	56	28 (50.0%)	28 (50.0%)
^aChi-square test, ^bMean age, ^cMean tumor size;

Selection of TROAP Expression Cutoff Value

Immunohistochemical staining showed that TROAP was mainly located in the cytoplasm of PSC (Fig. 3A). To choose an ideal cutoff score for this protein for further analysis, each clinicopathological parameter was analyzed using a receiver operating characteristic (ROC) curve (Fig. 3B). More than or equal to the obtained cutoff value was considered high expression of TROAP, whereas expression below the cutoff value was considered as low expression. According to this method, we found that clinical stage was the optimal clinicopathological factor (Fig. 3BⅠ). On the basis of this outcome, a score of 125 was identified as the suitable cutoff value for TROAP expression, and the corresponding sensitivity and specificity were 0.489 and 0.737, respectively, P < 0.05.

Association of TROAP Expression with the Clinicopathological Features of Patients with PSC

High expression of TROAP correlated significantly with P53 status, clinical stage, and N stage (P < 0.05), as assessed using the Chi-squared test. However, no significant correlation was found for the other clinical parameters (sex, age, smoking or not, tumor size, T stage, M stage, and recurrence.) (P > 0.05) (Table 1).

Association of P53 status with PSC Patients’ Clinicopathological Features

Among patients with PSC, 112 of 168 (66.7%) displayed aberrant P53 expression, with diffuse positive (≥ 60%) in 44 cases (39.3% of 112 cases), and completely absent staining in 68 cases (60.7% of 112 cases). Aberrant P53 expression was closely associated with TROAP expression (P = 0.033), and a significant negative correlation was observed between TROAP expression and P53 status using Pearson correlation analysis (P = 0.033, r = -0.164).

Relationship between TROAP Expression and Survival of Patients with PSC

In this study, we first evaluated the impact of all the clinicopathological factors and prognosis in patients with PSC using univariate and multivariate analysis (Tables 2 and 3). Univariate analysis demonstrated that among 168 patients with PSC, those with high expression of TROAP had significantly worse OS (P = 0.001, Table 2, Fig. 3CⅠ) and DFS (P = 0.012, Table 3, Fig. 3CⅡ). In addition, patients with aberrant expression of P53 were closely associated with worse OS in the 168 patients with PSC (P = 0.018, Table 2, Fig. 3CⅢ) and showed a statistical tendency to be associated with DFS among these patients (P = 0.063, Table 3, Fig. 3CⅣ). Cox risk regression model for multivariate analysis showed that TROAP protein expression (P = 0.028), P53 status (P = 0.024), and clinical stage (P = 0.002) could serve as independent prognostic factors for OS in patients with PSC (Table 2). Tumor size (P = 0.010) and clinical stage (P = 0.028) were judged to be independent prognostic predictors for DFS in patients with PSC, and TROAP protein expression (P = 0.080) showed a statistical tendency to be an independent prognostic factor for DFS in patients with PSC (Table 3).

Table 2

Univariate and multivariate analysis of clinicopathologic variables in 168 patients with PSC for overall survival
Variable		Univariate analysis		Multivariate analysis
Variable	All cases	Mean survival (mean ± SD)	P value ^a	Hazard ratio (95% CI)	P value ^a
Gender			0.751	0.744 (0.360–1.535)	0.423
Female	26	32.57 ± 5.44
Male	142	57.54 ± 6.05
Age (years) ^b			0.425	1.780 (1.097–2.888)	0.020
≤ 57.7	83	49.25 ± 6.23
> 57.7	85	56.00 ± 7.55
Tumor size ^c			0.114	1.093 (0.625–1.909)	0.755
≤ 4.7cm	71	62.75 ± 7.45
> 4.7cm	97	45.99 ± 7.88
Smoking			0.783	0.752 (0.439–1.290)	0.301
Yes	57	34.45 ± 3.93
No	111	57.02 ± 6.55
T stage			0.097	1.021 (0.576–1.812)	0.942
T1 - T2	101	59.31 ± 7.11
T3 - T4	67	50.57 ± 8.69
N stage			< 0.001	0.902(0.464–1.751)	0.760
N0	86	74.67 ± 7.73
N1 - N3	82	35.69 ± 6.43
M stage			< 0.001	1.808 (0.982–3.330)	0.057
M0	146	62.90 ± 6.21
M1	22	15.45 ± 3.71
Clinical stage			< 0.001	3.636 (1.634–8.092)	0.002
I-II	76	84.89 ± 8.26
III-IV	92	23.17 ± 2.56
Recurrence			0.001	1.455(0.896–2.363)	0.129
Yes	56	68.24 ± 7.77
No	112	27.72 ± 3.93
P53 status			0.018	1.825 (1.084–3.074)	0.024
Aberrant expression	112	42.23 ± 6.20
Wild type expression	56	78.43 ± 8.87
TROAP expression			0.001	1.731(1.061–2.823)	0.028
High	65	26.04 ± 3.23
Low	103	69.95 ± 7.31
^aChi-square test, ^bMean age, ^cMean tumor size;

Table 3

Univariate and multivariate analysis of clinicopathologic variables in 168 patients with PSC for disease-free survival
Variable		Univariate analysis		Multivariate analysis
Variable	All cases	Mean survival (mean ± SD)	P value ^a	Hazard ratio (95% CI)	P value ^a
Gender			0.224	1.970 (0.750–5.173)	0.169
Female	26	45.65 ± 6.24
Male	142	69.05 ± 6.94
Age (years) ^b			0.884	1.166 (0.669–2.031)	0.589
≤ 57.7	83	62.60 ± 6.57
> 57.7	85	67.82 ± 9.18
Tumor size ^c			0.001	2.291 (1.217–4.313)	0.010
≤ 4.7cm	71	82.02 ± 9.06
> 4.7cm	97	52.06 ± 9.38
Smoking			0.968	0.969 (0.517–1.814)	0.921
Yes	57	40.15 ± 4.40
No	111	70.85 ± 7.68
T stage			0.209	0.599 (0.302–1.188)	0.142
T1 - T2	101	72.49 ± 8.30
T3 - T4	67	68.45 ± 9.20
N stage			0.014	0.887(0.409–1.926)	0.763
N0	86	79.65 ± 8.11
N1 - N3	82	58.34 ± 9.43
M stage			0.002	1.693 (0.794–3.610)	0.173
M0	146	75.33 ± 7.08
M1	22	21.49 ± 5.09
Clinical stage			< 0.001	2.759 (1.118–6.808)	0.028
I-II	76	86.61 ± 8.64
III-IV	92	31.24 ± 3.72
P53 status			0.063	1.472 (0.795–2.726)	0.218
Aberrant expression	112	85.94 ± 9.58
Wild type expression	56	61.73 ± 7.92
TROAP expression			0.012	1.664(0.940–2.946)	0.080
High	65	85.15 ± 7.02
Low	103	33.06 ± 4.42
^aChi-square test, ^bMean age, ^cMean tumor size;

Risk stratification analysis demonstrated that patients with high expression of TROAP were significantly associated with to unfavorable OS (P = 0.038, Fig. 3CⅤ), but not strongly associated with worse DFS (P = 0.176, Fig. 3CⅥ) in patients with PSC with aberrant P53 expression. There were significant statistical differences for OS and DFS for patients with PSC among the three groups including the low risk group with low expression of TROAP and wild-type expression of P53, the intermediate risk group with either high expression of TROAP or aberrant expression of P53, and the high risk group with both high expression of TROAP and aberrant expression of P53. Patients in high risk group experienced the worst OS (P < 0.001, Fig. 3CⅦ) and DFS (P = 0.006, Fig. 3CⅧ) among the three groups.

PSC is characterized by poorly differentiated carcinoma with an inferior survival outcome because of a high rate of resistance to conventional first-line platinum-based chemotherapy [49]. Surgical resection, when feasible, remains the most important approach to systematic treatment. A clinical staging system is now being used widely to predict the prognosis of patients with PSC worldwide; however, patients still have worse outcomes across all stages of the disease, because they present with many adverse features, such as higher grade, larger volume, and more advanced clinical stage [42]. Therefore, it remains necessary to develop new objective strategies that can effectively distinguish between patients with relatively better or worse prognosis. Previous studies demonstrated several aberrantly mutated genes in PSC, including the MET exon 14 skipping mutation, which causes increased oncogenic signaling of the MET receptor, leading to tumor growth and proliferation [21], and a dramatic response to MET inhibition has been noted [22, 28]. Two recent studies found that 30–40% of PSC cases harbored KRAS mutations that are associated with poor prognosis [29, 43]. However, patients with neither of these deleterious molecular changes were proven to be insensitive to targeted therapy in the clinic. Novel molecular markers that could identify tumor recurrence and/or risk assessment are urgently needed to select new treatments.

TROAP is a cytoplasmic protein regulated by the microtubular cytoskeleton that plays a prominent role in early embryo implantation, in which it mediates the process of cell mitosis and tumor progression [12, 50]. TROAP is a crucial regulator that controls cell proliferation, invasion, and migration via multiple signaling pathways. Recently, TROAP was observed to enhance the invasion of human colorectal cells via a mechanism involving high mobility group box 1 (HMGB1)/ receptor for advanced glycosylation end products (RAGE) [16], and seemed to be able to control the proliferation of prostate cancer cells through the Wnt family member 3 (WNT3)/survivin signaling pathway [51]. In addition, increased expression of TROAP correlated with the development and progression of diverse human cancers, including ovarian cancer [1], gastric cancer [19], breast cancer [25], and hepatocellular carcinoma [18]. These studies also showed that silencing of TROAP inhibited the proliferation and migration ability of gastric cancer and prostate cancer cells. Nevertheless, the expression of TROAP and its prognostic value in PSC remain unclear. In addition, the underlying mechanism by which TROAP affects prognosis requires further investigation. The results of the present study form the basis for further exploration of the in-depth mechanisms for the progression and metastasis of PSC mediated by TROAP, by identifying the receptors, adapters, target proteins, and pathways.

Meanwhile, previous NGS-based studies showed that in PSC, the highest rate of TP53 mutation ranged from 57.1 to 74% [27–29, 39, 43]. The examination of P53 status has used inexpensive IHC staining as a surrogate marker in many studies of human cancers [3, 23, 52]. In view of this, the expression of P53 in PSC and its prognostic value remain to be investigated. Moreover, the correlation between TROAP expression and P53 status based on IHC staining in PSC should also be evaluated.

In the present study, we investigated TROAP and P53 protein expression in 168 PSC tissues. The results revealed that 65 patients with PSC were classified as having high expression of TROAP, and aberrant expression rate of P53 was 66.7% (112/168). Although we examined P53 status using IHC as a surrogate marker, the rate of 66.7% is still located within the range 57.1–74% reported previously. It also showed that our results are credible to detect P53 mutation using IHC staining in PSC. Further NGS experiments should be done using our samples to confirm the IHC-based assessment of P53 status. We demonstrated that TROAP protein expression is significantly associated with P53 status. cBioPortal for Cancer Genomics identified a significant negative relationship between TROAP mRNA expression and P53 status. Online analysis using iBioSci Tools v5.0 predicted that TROAP’s function is closely related to the signaling pathways involving P53. GeneMANIA software predicted that the interaction of P53-ERBB4-TROAP or P53-MKI67-TROAP could play an important role in the regulation of TROAP expression, indicating the important function of P53. Therefore, we speculated that P53 status could serve as a candidate predictive marker for the response to targeted therapies involving TROAP.

Further correlation analyses showed that high expression of TROAP correlated strongly with clinical stage, indicating that TROAP might promote the proliferation and differentiation of PSC. Moreover, association analysis of TROAP expression with clinicopathological parameters suggested that high expression of TROAP was significantly linked to lymph node metastasis, which agreed with the results of previous research [9]. Our findings support the view that TROAP acts as an oncogene in the progression and development of PSC, probably dependent on P53 status. Collectively, the data showed that TROAP functions to promoter malignant transformation and might be activated in human cancers, possibly through P53 signaling pathways. In addition, high TROAP expression was closely related to the poor prognosis of patients with PSC as an independent prognostic factor, which was similar to the results of previous studies [9, 17], in which high TROAP expression correlated with adverse survival in lung adenocarcinoma and liver cancer. This suggested that activated TROAP might lead to the aggressive biological behavior of cancers and could be considered as a critical biomarker to assess prognosis in various human cancers. Univariate analysis showed that patients with aberrant expression of P53 had shortened survival compared with that of patients with wild-type P53 expression. This was consistent with the results of previous studies in which the presence of any P53 mutation resulted in worse survival in patients with squamous cell carcinoma of the head and neck [37]. In patients with ovarian cancer, the prognostic significance of aberrant P53 status, assessed using IHC or mutational analysis, was related to poor prognosis [10]. These observations suggested that P53 mutations might be the critical drivers in the progression of squamous cell carcinoma of the head and neck, ovarian cancer, and PSC. However, the predictive value of aberrant P53 aberrant lacked significance in terms of clinical outcome in patients with colon cancer [33]. This indicated that other gene mutations, such as KRAS mutations, might be the drivers leading to the development of colon cancer.

From the results mentioned above, an explanation is required as to why aberrant P53 expression or high expression of TROAP are strongly associated with worse prognosis in patients with PSC, whereas aberrant P53 expression is significantly associated with low expression of TROAP. In our study, aberrant P53 expression presumably results from the presence of P53 mutations. Previous studies reported that several types of P53 mutation led to the accumulation of mutated P53 protein in the nuclei of tumor cells that still exerted their function as a tumor suppressor [2, 32]. Therefore, the mutation type that promotes tumorigenesis and its relationship with TROAP expression requires further exploration in patients with aberrant P53 expression.

Risk stratified analysis demonstrated that high TROAP expression was significantly related to unfavorable OS in patients with PSC with aberrant P53 expression. Thus, identification of this subset of patients with aberrant P53 expression and high TROAP expression, might allow more accurate prediction of their prognosis and provide opportunities for improved individual treatment, including recovery of P53 gene function and/or targeted therapy associated with TROAP. Furthermore, there were significant statistical differences for OS and DFS for patients with PSC among the three risk groups, including the low risk group (low TROAP expression and wild-type P53 expression, the intermediate risk group (either high TROAP expression or aberrant expression of P53), and the high risk group (both high TROAP expression and aberrant P53 expression). Patients in the high risk group had a worse prognosis than the other two groups. These data suggested that patients harboring high expression of TROAP and aberrant expression of P53 might require more radical treatment, especially targeted therapy for TROAP protein and/or the recovery of P53 gene function.

In a conclusions, we found that the analysis of TROAP expression and P53 status using IHC might serve as an effective tool to determine those patients with PSC who are at increased risk of tumor progression and metastasis. We also showed that high expression of TROAP is an independent biomarker of unfavorable prognosis in PSC, and in combination with P53 status, could effectively identify patients at high risk of having a worse prognosis, which will help the development of new therapeutic targets and benefit individual treatment.

TROAP, Trophinin-associated protein;

PSC, pulmonary sarcomatoid carcinoma;

ROC, receiver operating characteristic.

IHC: Immunohistochemistry;

AUC: Area under the curve;

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki and approved by the Institute Research Medical Ethics Committee of Sun Yat-Sen University Cancer Center (YB2018-016), Who granted permission to access the raw data from the Research Data Deposit public platform of Sun Yat-sen University Cancer Center. All of the samples were anonymized. No written or verbal informed consent was obtained for use of the retrospective data from the patients in the current work, since most of them were deceased and it was not deemed necessary by the Ethics Committee of Sun Yat-Sen University Cancer Center, who waived the need for consent.

Consent for publication

Not applicable.

Data availability statement

All data relevant to the study are included in the article. The datasets generated and/or analysed during the current study are available in the Research Data Deposit public platform (www.researchdata.org.cn) of Sun Yat-sen University Cancer Center. But restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. The datasets generated are available from the corresponding author on reasonable request.

The datasets analyzed for this study can be found in the GEPIA [http://gepia.cancer-pku.cn/detail.php], UALCAN [http://ualcan.path.uab.edu/analysis] and cBioPortal [http://www.cbioportal.org].

Competing interests

The authors declare that they have no competing interests.

Funding information

National Natural Science Foundation of China (81902420), and Youth Innovation Promotion Program of Sun Yat-sen University Cancer Center（QNYCPY22）, Guangdong Esophageal Cancer Institute Science and Technology Program (Q201903).

Authors' contributions

RZL and JWC designed this research. JWC, ZZL, SSL and XKZ acquired and analyzed the data. XKZ, JWC, ZZL and SSL performed all the experiments and draft the manuscript. SJW, JL, SSL and XHL collected the data. All authors have approved the submitted version (and any substantially modified version that involves the author's contribution to the study). All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Acknowledgements

Not applicable.

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No competing interests reported.

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Clinicopathological and prognostic significance of Trophinin-associated protein expression and its relationship with P53 status in pulmonary sarcomatoid carcinoma: A retrospective multicenter study based on bioinformatic analysis

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Abstract

Figures

Highlights

Introduction

Materials And Methods

Bioinformatic analysis based on online database

Patients and tissue specimens

Immunohistochemistry (IHC)

IHC evaluation

Selection of a cutoff value for TROAP expression

Statistical analysis

Results

The results of Bioinformatic analyses based on online databases

Patients’ characteristics

Selection of TROAP Expression Cutoff Value

Association of TROAP Expression with the Clinicopathological Features of Patients with PSC

Association of P53 status with PSC Patients’ Clinicopathological Features

Relationship between TROAP Expression and Survival of Patients with PSC

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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