| Abstract|| |
Background: Yin Yang 1 (YY1), the multifunctional transcription factor, has recently been assigned biological properties related to human malignancies. YY1 can facilitate both tumor suppression and tumor growth. The conflicting role of YY1 in human malignancies is not yet fully explained. Objective: In this study, we determined the clinicopathologic significance and prognostic role of YY1 in stage III colorectal cancer (CRC). Materials and Methods: YY1 expression was evaluated immunohistochemically in tissue microarray from 345 CRCs. YY1 expression was scored by the proportion of tumor cells with nuclear staining into 4 scores (0, none; 1+, ≤10%; 2+, 10 to ≤25%; 3+, >25%). A score of 0 and 1 were considered as loss of expression. Results: Loss of YY1 expression was observed in 49 (14.2%) out of 345 CRCs and was associated with larger tumor size (P = 0.004), tumor deposit (P = 0.008), and higher pathologic tumor (pT) stage (P = 0.004). In stage III group, loss of YY1 expression was associated with larger tumor size (P = 0.027) and tumor deposit (P = 0.011). Kaplan–Meier survival curves revealed no significant difference between patients with YY1 loss and patients with intact YY1 in both cancer-specific survival and recurrence-free survival (P = 0.330 and P = 0.470, respectively). In American Joint Committee on Cancer (AJCC) stage subgroup, loss of YY1 expression was associated with poor recurrence-free survival in AJCC stage III CRC (P = 0.038). Conclusion: Loss of YY1 expression was significantly associated with aggressive phenotypes and poor patient outcome in AJCC stage III CRC.
Keywords: Colorectal adenocarcinoma, immunohistochemistry, prognosis, YY1
|How to cite this article:|
Kim H, Bang S, Jee S, Park S, Kim Y, Park H, Jang K, Paik SS. Loss of YY1 expression predicts unfavorable prognosis in stage III colorectal cancer. Indian J Pathol Microbiol 2021;64, Suppl S1:78-84
|How to cite this URL:|
Kim H, Bang S, Jee S, Park S, Kim Y, Park H, Jang K, Paik SS. Loss of YY1 expression predicts unfavorable prognosis in stage III colorectal cancer. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jun 23];64, Suppl S1:78-84. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/78/317936
| Introduction|| |
Despite breakthrough progress in the treatment of patients with colorectal cancer (CRC), CRC ranks the fourth leading cause of cancer-related death. Surgical resection is the first choice of curing CRC, and adjuvant systemic therapy including molecular targeted drugs can improve patient survival. Although the median survival of patients with CRC has notably increased in the past 20 years, when diagnosed, 50% to 60% of tumors have metastasized and resulted in harsh patient survival. Although the majority of CRC patients are classified with AJCC stage III, in which tumor carries at least one metastatic lymph node, these patients constitute a heterogeneous population and have various prognosis. Numerous studies have focused on the identification of new predictive biomarkers and classify subgroups more likely to response from different treatment strategies.
Yin Yang 1 (YY1) is a transcriptional protein that is involved in multiple biological functions including cell-cycle progression, cell proliferation, differentiation, and apoptosis. YY1 has four zinc fingers, that use zinc ions to stabilize its structures, which are attached to its binding domain, carboxylic terminals. As the name “Yin Yang” implies, YY1 can act as an activator or as a suppressor to regulate the expression of different genes depending on the DNA-binding sites. Many studies investigated the role of YY1 in tumor and its significance as a prognostic factor. Most studies have reported the oncogenic role of YY1 in the tumorsamples including breast cancer, liver cancer, prostate cancer, and ovarian cancer.,,, However, some studies demonstrated the tumor suppressive role of YY1 in follicular lymphoma, pancreatic cancer, and nasopharyngeal carcinoma.,, Altogether, the accumulated data of YY1 suggest that YY1 could be an important regulator of carcinogenesis, but the underlying mechanism of YY1 is still unclear.
In CRC, several studies have examined the role of YY1 as a regulator of carcinogenesis.,, Ye et al. demonstrated that two transcriptional factors, YY1/ARAP1-AS1 axis, promoted tumor cell migration, invasion, and epithelial-mesenchymal transition (EMT) process. Zhang et al. disclosed the overexpression of YY1 in CRC and the prognostic significance of YY1 as a poor survival biomarker. Chinnappan et al. provided evidence of YY1 overexpression in a series of human CRC samples and excluded the possibility of chromosomal translocation and gene amplification as underlying mechanisms. In dichotomized survival analysis, low YY1 expression was a poor prognostic factor, however, this comparison was not statistically significant.
In the present study, we investigated the clinicopathologic significance of YY1 expression and its association with survival rates in stage III CRC.
| Materials and Methods|| |
From January 2005 to December 2010, 345 patients underwent curative surgery for primary CRC at Hanyang University Hospital. Patients who had received neoadjuvant chemotherapy or radiotherapy or those who had recurrent CRC were excluded. To determine the clinical characteristics, we reviewed the medical records: follow-up interval, age, sex, survival status, recurrence status, and postoperative adjuvant treatment. Two surgical pathologists (H. K. and S. P.) reviewed the pathologic diagnosis reports and hematoxylin and eosin (H and E)-stained slides to determine the pathologic characteristics and to confirm the diagnosis. Pathologic parameters including the tumor-node-metastasis (TNM) stage (8th AJCC) were determined according to a protocol for examining specimens from patients with primary adenocarcinoma of the colon and rectum., Pathologic characteristics included tumor size, gross type, tumor location, histologic grade (grade 1, >95% gland formation; grade 2, 50%–95% gland formation; grade 3, <50% gland formation; grade 4, no gland formation or mucin), lymphatic invasion, vascular invasion, perineural invasion, tumor deposit (a tumor focus in the pericolic/perirectal fat or in adjacent mesentery without identifiable lymph node tissue or vascular structure), tumor budding (the presence of single cells or small clusters of less than five cells at the advancing front of the tumor), tumor, node, metastasis classification system (TNM) stage, and microsatellite instability (MSI) status. This study was approved by the Institutional Review Board of the Hanyang University Hospital (HYUH 2019-11-008-002), and the requirement for informed consent was waived.
Tissue microarray construction
Manual tissue microarrayer (Unitma, Seoul, Korea) was used for tissue microarray construction from archival formalin-fixed, paraffin-embedded tissue blocks. We marked a representative tumor lesion by light microscopy of H and E-stained sections. Tissue cylinders with 2 mm diameter were punched from a previously marked area of tumor lesion on the donor block and transferred to the recipient block (Unitma).
Microsatellite status was determined using a previously described panel of five National Cancer Institute workshop-recommended consensus microsatellite markers (BAT25, BAT26, D2S123, D17S250, and D5S346). MSI-High was defined as a shifting of microsatellites at two or more markers. A shifting of microsatellites at one marker was defined as MSI-Low. Microsatellite stable (MSS) and MSI-L were classified as nonMSI-High.
Immunohistochemical study and interpretation
The immunohistochemical study for YY1 expression was performed with 4-μm-thick sections from tissue microarray (TMA) blocks using the Ventana Benchmark XT automated staining system (Ventana Medical Systems, Tucson, AZ, USA) according to the manufacturer's protocol. The rabbit monoclonal anti-YY1 (1:200, ab-109237, Abcam) antibody was used for immunohistochemical staining. YY1 expression was scored by the proportion of tumor cells with nuclear staining into 4 scores according to the previously described system (0, none; 1+, ≤10%; 2 +, 10 to ≤25%; 3 +, >25%). A score of 0 or 1 was considered as loss of expression. Representative microphotographs are shown in [Figure 1].
|Figure 1: Representative microphotographs of YY1 expression in colorectal cancer. Loss of expression (a) and intact expression (b) (original magnification, × 200)|
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Statistical analysis was performed using a SPSS software version 21 (IBM Corp., Armonk, USA). The Chi-square and Mann–Whitney U tests were used to evaluate the association between YY1 expression and other clinicopathologic characteristics including age, sex, gross type, tumor size, histologic grade, lymphatic invasion, vascular invasion, perineural invasion, tumor deposit, tumor budding, TNM stage, and MSI status. Cancer-specific survival (CSS) was defined as the time interval between the date of curative surgery and the date of death due to CRC. Recurrence-free survival (RFS) was defined as the time interval between the date curative surgery and the date of recurrence. Survival analysis was performed using Kaplan–Meier survival curves, the log-rank test, and the Cox proportional hazard regression model. Two-tailed P values <0.05 were considered statistically significant.
| Results|| |
Baseline characteristics of patients
The baseline characteristics of patients are summarized in [Table 1]. Median follow-up period was 108 months (range 1–165), mean age at surgery was 63.5 years (range 28–89), and 214 (62.0%) patients were men with a male-to-female ratio of 1.63:1. Pathologic analyses revealed that 28 tumors (8.1%) were histologic grade 1, 158 (45.8%) were grade 2, 143 (41.4%) were grade 3, and 16 (4.6%) were grade 4. According to the 8th AJCC staging system, 51 (14.8%) were stage I, 108 (31.3%) were stage II, 159 (46.1%) were stage III, and 27 (7.8%) were stage IV. Among 345 cases, 318 (92.2%) were nonMSI-High and 27 (7.8%) were MSI-High. Distant metastasis was observed in 27 (7.8%) patients at the time of initial diagnosis, 77 (22.3%) had experienced relapse or metastasis during the follow-up, and 163 (47.2%) had died due to colorectal adenocarcinoma. Among 345 cases, 161 (46.7%) received additional postoperative treatment and 184 (53.3%) did not receive additional postoperative treatment.
Correlations between loss of YY1 expression and clinicopathologic characteristics
In total cases, loss of YY1 expression was observed in 49 (14.2%) of 345 cases. Loss of YY1 expression was significantly correlated with larger tumor size (P = 0.004), tumor deposit (P = 0.008), and higher pathologic tumor (pT) stage (P = 0.004) [Table 2]. In AJCC stage III CRC, loss of YY1 expression was observed in 22 (13.8%) of 160 cases and correlated with larger tumor size (P = 0.027) and tumor deposit (P = 0.011) [Table 3].
|Table 2: Correlation between YY1 expression and clinicopathologic factors in colorectal adenocarcinoma|
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|Table 3: Correlation between YY1 expression and clinicopathologic factors in AJCC stage III colorectal adenocarcinoma|
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Prognostic role of loss of YY1 in CRC
There was no significant difference between the groups with loss of YY1 expression and the groups were with intact YY1 expression for both CSS and RFS [P = 0.330 and P = 0.470, respectively; [Figure 2]a and [Figure 2]b. In stage III CRC, there was no significant difference in CSS [P = 0.247; [Figure 2]c], however, loss of YY1 expression was associated with shorter RFS [P = 0.038; [Figure 2]d]. Subgroups of other stages (I, II, and IV) showed no significant correlation in survival analyses. The associations of conventional prognostic factors in patient survival were explored. Univariate Cox regression analysis revealed that histologic grade, vascular invasion, and tumor deposit were a poor prognostic factor in both CSS and RFS [Table 4]. Multivariate Cox regression analysis demonstrated that vascular invasion and tumor deposit were a poor prognostic factor in CSS and only vascular invasion was a poor prognostic factor in RFS [Table 4]. Loss of YY1 expression was a predictor of poor RFS by univariate analysis (P = 0.043), however, it was not an independent prognostic factor in multivariate analysis (P = 0.102) [Table 4].
|Figure 2: Survival analyses of cancer-specific survival (CSS) and recurrence-free survival (RFS) in colorectal cancer (CRC) patients according to YY1 expression. No significant difference in CSS or RFS was observed in all CRC patients (a and b). There was no significant difference in CSS (c), however, loss of YY1 expression was associated with shorter RFS (d) in AJCC stage III CRC patients|
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|Table 4: Univariate and multivariate analyses of clinicopathologic factors in AJCC stage III colorectal adenocarcinoma|
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| Discussion|| |
In the present study, we evaluated the YY1 expression in 345 samples of CRC and investigated the correlation between the loss of YY1 expression and clinicopathologic parameters. Loss of YY1 expression was significantly correlated with aggressive phenotypes including larger tumor size, tumor deposit, and higher pT stage. In survival analyses, loss of YY1 expression revealed no prognostic effect in the total cohort, however, loss of YY1 expression was a poor prognostic factor of RFS in stage III CRC.
YY1 is a protein, which belongs to GLI-Krüppel family and regulates other genes mainly through the carboxylic terminal zinc finger region. YY1 is involved in divergent biologic processes including embryogenesis, cell proliferation, differentiation, and apoptosis. In addition, YY1 regulates numerous genes involved in tumorigenesis including both oncogenes and tumor suppressor genes depending on its binding context and tumor types. YY1 positively regulated well-known oncogenes including c-Myc and VEGF, as well as tumor suppressor genes including HLJ1 and BRACA1.,,, Increased YY1 protein expression has been reported in breast cancer, prostate cancer, liver cancer, and ovarian cancer.,,, Besides, reduced YY1 expression was also observed in osteosarcoma and melanoma.,
Most studies have reported the oncogenic role of YY1 in tumor samples including breast cancer, liver cancer, prostate cancer, and ovarian cancer.,,, In breast cancer, YY1 was reported as an activator of LINC00673, which promotes tumor cell proliferation via the miR-515-5p/MARK4/Hippo signaling pathway. In liver cancer, Dong et al. found that YY1 reduces the sensitivity of hepatocellular carcinoma (HCC) cells to histone deacetylase inhibitor (HDACi), which promotes apoptosis of tumor cells and inhibits proliferation of tumor cells. Kashyap et al. disclosed that YY1 expression was upregulated in human prostate cancer and YY1 was involved in drug resistance and development of epithelial-mesenchymal transition. In ovarian cancer, YY1 was reported as a target for miR-381, and YY1 suppression results in the inhibition of cell proliferation, invasion, and migration of epithelial ovarian cancer. These oncogenic effects of YY1 in each organ are consistent with the following review of YY1's role in tumoriogenesis: YY1 activates well-known oncogenes including c-Myc and ERBB2 and antagonizes the several tumor suppressors including p53 and p14ARF.
Some studies demonstrated the tumor suppressive role of YY1 in follicular lymphoma, pancreatic cancer, and nasopharyngeal carcinoma.,, Naidoo et al. performed the quantum dot labeled immunohistochemistry to quantify the YY1 protein in follicular lymphoma samples. High YY1 expression was associated with longer survival in follicular lymphoma patients. In pancreatic cancer, YY1 was reported as a tumor suppressor, which inhibits tumor cell proliferation and migration. Liu et al. elucidated that YY1 downregulates the cyclin-dependent kinase inhibitor 3 gene (CDKN3) by binding to CDKN3 promoter and reduced CDKN3 expression decreases the formation of murine double minute 2 (MDM2)-P53 complex, which upregulates the P21 expression. In nasopharyngeal carcinoma, YY1 overexpression was associated with tumor cell proliferation and cell-cycle progression. Li et al. found that ectopic YY1 expression inhibits the transcriptional activity of c-Myc, as well as the promoter activity of the c-Myc target gene, microRNA-141. Levon et al. reviewed recent reports of YY1 function in tumoriogenesis and reported that various mechanisms including BRACA1 stimulation, increased Bax transcription, and induction of heme oxygenase-1, which are involved in tumor suppression.
There are several studies describing the oncogenic role of YY1 in CRC. Zhang et al. reported that miR-7 binds to YY1 and inhibits its expression, which results in cellular apoptosis and the reduction of cellular proliferation in the CRC cell line. Ye et al. revealed that YY1 induces the upregulation of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 (ARAP1) antisense RNA1 (ARAP1-AS1) and this YY1/ARAP1-AS1 axis promotes cell migration, invasion, and EMT process through Wnt/β-catenin pathway. Zhu et al. focused on O-GlcNAcylation, which plays a pivotal role in the carcinogenesis of CRC. This study revealed that YY1 is O-GlcNAcylated by O-GlcNAc transferase and stimulates tumorigenesis by targeting oncoproteins, Solute carrier family 22 member 15 (SLC22A15) and Aralkylamine N-acetyltransferase (AANAT).
Recently, Bonavida et al. reported the prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers using the cancer genome atlas (TCGA) database. They disclosed that YY1 protein and YY1 mRNA were overexpressed in CRC compared to normal colonic tissues. However, one study included in this analysis showed unexpected results that lower YY1 protein expression was associated with poor patient outcomes in colorectal cancer. Our result was similar to their unexpected result. In our study, loss of YY1 expression was a poor prognostic factor of RFS in stage III CRC. The mechanism of these opposing outcomes as tumor promoter vs. tumor suppressor is not completely clear. The various proteins with which YY1 interacts might determine its function as a transcriptional activator or repressor as well as its role as a tumor promoter or suppressor.
We have identified the actual protein expression of YY1 in a significant large cohort of colorectal cancer (345 patients) and correlated it with various clinicopathologic parameters. This is the only study in CRC determining the prognostic role of YY1 according to the AJCC stage. However, there are several limitations. We retrospectively obtained patient data and selection bias was not completely excluded. And we only performed one method of using immunohistochemistry to detect YY1. Other modalities using either a western blot or a PCR that detect tissue proteins are required to support our findings. In addition, the detailed molecular mechanism explaining the tumor suppressive role of YY1 in CRC was not studied. As described above, interaction with other proteins might bring out the tumor suppressive function of YY1. Wang et al. revealed that YY1 upregulates the well-known tumor suppressor, HLJ1 and inhibits cancer cell invasion. Further studies are warranted to identify the tumor suppressive function of YY1 in CRC.
In conclusion, loss of YY1 expression was significantly associated with aggressive phenotypes and shorter RFS in stage III CRC. Further molecular investigations or larger cohort studies are needed to clarify the exact mechanism of YY1 protein.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Seung Sam Paik
Department of Pathology, College of Medicine, Hanyang University, 222 Wangsimri-ro, Sungdong-ku, Seoul - 04763
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]