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How far the research is from the precise mechanism of Yang 1-associated protein 1 in gastric adenocarcinoma? Dina Johar* Department of Biochemistry and Nutrition, Faculty of Women for Arts, Sciences and Education, Heliopolis, Cairo, Egypt *Dina Johar, PhD Department of Biochemistry and Nutrition Faculty of Women for Arts, Sciences, and Education Ain Shams University, Cairo, Egypt Phone:+2 01060782045 Email: dinajohar@gu.edu.eg • To whom correspondence should be addressed Abstract The Yang 1-associated protein 1 (YY1AP1) is frequently overexpressed or activated in gastric cancer and is linked to more aggressive disease, poorer prognosis, and metastasis. Although YY1AP1 signaling contributes to pathways that promote proliferation, epithelial–mesenchymal transition, stemness, and drug resistance, the precise mechanism of YY1AP1 in gastric cancer has not been precisely defined. In this commentary, we focus on recent findings on the functional mechanisms of YY1AP1 in gastric adenocarcinoma. The commentary is a significant step forward in understanding the nuanced approach to managing mortality rate in gastric cancer patients, offering valuable insights for clinical decision-making. Keywords: Yang 1-associated protein 1, Gastric adenocarcinoma, Prognosis, Mortality. Core tip YY1AP1 is best understood as both a prognostic biomarker and a functional oncogenic driver in gastric cancer, with evidence pointing to its role in tumor growth, invasion, metastasis, stemness, and treatment resistance. Background YY1AP1 overexpression has been associated with progression, lymph node metastasis, and poor prognosis in gastric carcinoma [1]. Studies found that YY1AP1 activation or high expression predicts worse survival and, in some cohorts, chemoresistance to adjuvant therapy [2-4]. In peritoneal metastatic gastric adenocarcinoma, YY1AP1-high tumor cells showed stem-cell-like properties and were clinically relevant as metastatic drivers [5]. YY1AP1 appears to drive gastric cancer biology through canonical Hippo pathway dysregulation and downstream transcriptional programs that support growth and invasion [6, 7]. Mechanistic studies show YY1AP1 can enhance proliferation, migration, invasion, EMT, and metastasis through signaling changes involving ERK, β-catenin, E-cadherin, vimentin, and lncRNA networks (Sun et al., 2016). Several upstream regulators and interacting partners contribute to YY1AP1 activation in gastric cancer, including H. pylori CagA, NUSAP1, SLC35B4, and CPNE3[7-11]. In gastric adenocarcinoma metastasis, YY1AP1 also linked with altered fatty-acid oxidation and cancer stem cell phenotypes [12]. The recent study of Gu et al. (2026)[13] investigates the clinical significance and functional mechanisms of YY1AP1 in gastric adenocarcinoma, finding its upregulation correlates with poor prognosis and aggressive tumor behavior. It critically assesss the argumentation within the article, focusing on the clarity of the research gap, the strength of the contribution claims, the justification of methods, the alignment of results with the discussion, and the thoroughness of the stated limitations. It also clearly articulates its perceived novelty regarding YY1AP1's role as an independent prognostic factor in gastric adenocarcinoma and its comprehensive investigation. Particularly, YY1AP1’s expression patterns, clinical relevance, biological functions, i.e. in proliferation, migration, gene modulation, and its status as an independent prognostic factor of gastric cancer. The stated aims are highly testable, as evidenced by the detailed methods employed, i.e. immunohistochemistry, RT-qPCR, survival analysis, or in vitro experiments. The authors’ argumentation generally establishes a clear research gap and strong contribution claims, supported by a combination of clinical, in vitro, and bioinformatic data. However, as compared to the aforementioned extensive literature on the specific mechanism/signaling of YY1AP1 in gastric cancer, there are opportunities to enhance methodological justification, ensure stricter alignment between results and discussion, and deepen the analysis of limitations. The Gu et al.[13] study provides sufficient detail for most experimental procedures and statistical analyses. However, specific justifications for certain choices, such as the selection of the MKN45 cell line or the specific online datasets, could be strengthened to enhance the methodological rigor and transparency. For example, “MKN45 is a well-characterized...mechanisms of gastric cancer." This provides a good, albeit brief, justification for using the MKN45 cell line, linking its characteristics to the study's aims. To further strengthen, it worth it to mention if this cell line accurately represents specific subtypes of gastric cancer relevant to the study. Another example, "A semi-quantitative scoring system...combined assessment." The description of the Immunohistochemistry as a scoring system is somewhat vague, lacking specific criteria for how "combined assessment" was performed or how the cutoff for high/low expression was determined. Providing a more precise description of the scoring system and the methodology for categorizing samples is so important. A third example, "The normality of data distribution...Shapiro-Wilk test." While stating the use of the Shapiro-Wilk test, the consequences of non-normal distribution (i.e., use of non-parametric tests) are not explicitly mentioned for cellular assays, which could impact the choice of t-test/ANOVA. It is important to clarify how non-normal data was handled, or confirm that all cellular assay data met normality assumptions for parametric tests. Further, "To further validate and extend...and GSE62254." The choice of these specific online datasets is not justified. It is unclear why these particular datasets were selected and if they represent a diverse or comprehensive set of gastric cancer patient cohorts. Elaborating on the criteria used for selecting these online datasets (i.e., sample size, type of data available, clinical annotation, specific gastric cancer subtypes if applicable) helps the reader. While many of the study claims are correlational, the in vitro experiments aim to establish more direct functional roles. Distinction between correlation and causation more precisely, especially when discussing clinical observations versus experimental manipulations is key. For example, "YY1AP1 significantly influences the pathogenesis... by modulating key cancer-related pathways." This statement implies a direct causal influence, which is partially supported by in vitro modulation of p21, c-myc, and snail, but the broader "pathogenesis" is complex and likely involves multiple factors. While in vitro data supports modulation of some pathways, the term "significantly influences the pathogenesis" might be too strong for the overall conclusion without more comprehensive mechanistic studies. Another example, "Our multivariate analysis identified high YY1AP1 expression... a novel finding in gastric adenocarcinoma." While multivariate analysis identifies independent prognostic factors, the wording implies a direct causal "role" in progression, which is an inference from prognostic value. It worth clarifying that high YY1AP1 expression is associated with poor outcomes and serves as an independent prognostic factor, rather than implying it causes the poor outcome in the context of clinical correlation. The in vitro data strengthens the causal link for proliferation/invasion, but this specific statement is about clinical correlation. The study acknowledges several important limitations, particularly regarding its retrospective design and generalizability, and points to the need for causal relationship studies. However, some limitations, such as the sample size for fresh tissue analysis or the lack of mechanistic studies beyond gene expression changes, could be elaborated or more explicitly stated. I.e., "The retrospective design and the specific patient cohort limit the generalizability of the results." The limitation is stated, but the extent of this limitation on the current conclusions is not fully elaborated. Discussing how this limitation might affect the confidence in YY1AP1 as a prognostic biomarker until prospective validation is inevitable. Accordingly, this suggests while promising, that the prognostic value of YY1AP1 requires validation in larger, prospective, and multi-center cohorts before clinical application. Also, while acknowledged, “The exact molecular mechanisms through which YY1AP1 affects tumor biology... require further elucidation." The discussion could briefly connect this to how the current findings should be interpreted, i.e., as strong associations and initial functional insights, but not definitive mechanistic pathways yet. Therefore, their study provides strong correlational and initial functional evidence, but the precise molecular cascade remains to be fully mapped. This points out the need for more in-depth mechanistic studies (e.g., rescue experiments) to establish direct causality, which is a significant limitation for a study proposing functional roles. Further, "A total of 118 paraffin-embedded and 29 fresh gastric adenocarcinoma samples were analyzed." and "Fresh gastric adenocarcinoma and adjacent nontumor tissues were snap-frozen..." Clearly, the number of fresh samples (29) for RT-qPCR is relatively small compared to the FFPE samples (118) for immunohistochemistry. This smaller sample size for mRNA analysis could be a limitation, especially if there were discrepancies or if it impacts the robustness of mRNA findings. This is not explicitly discussed in the limitations. Adding the smaller sample size for fresh tissue analysis (RT-qPCR) as a limitation, acknowledging its potential impact on the generalizability or statistical power of mRNA-level findings. Declarations Funding This commentary did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The author declare that no honorarium, grant, or other form of payment was given to anyone to produce the manuscript. Conflict of interest The author declares no conflict of interest exists. Consent to publish Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Acknowledgment N/A References [1] Hu X, Xin Y, Xiao Y, Zhao J. Overexpression of YAP1 is correlated with progression, metastasis and poor prognosis in patients with gastric carcinoma. Pathol Oncol Res. 2014;20:805-11. [2] Yu D, Chen Y, Luo M, Peng Y, S. Y. Upregulated Solute Carrier SLC39A1 Promotes Gastric Cancer Proliferation and Indicates Unfavorable Prognosis. Genet Res (Camb) 2022. [3] Geng ZH, Du JX, Chen YD, Fu PY, Zhou PH, Qin WZ, et al. YY1: a key regulator inhibits gastric cancer ferroptosis and mediating apatinib-resistance. Cancer Cell Int. 2024;12:71. [4] Lee KW, Lee SS, Hwang JE, Jang HJ, Lee HS, Oh SC, et al. [5] Ajani JA, Xu Y, Huo L, Wang R, Li Y, Wang Y, et al. YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition. Gut. 2021;70:55-66. [6] Messina B, Lo Sardo F, Scalera S, Memeo L, Colarossi C, Mare M, et al. Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression. Cell Death Dis. 2023;14:21. [7] Guo H, Zou J, Zhou L, Zhong M, He Y, Huang S, et al. NUSAP1 Promotes Gastric Cancer Tumorigenesis and Progression by Stabilizing the YAP1 Protein. Front Oncol 2021. [8] Liu Z, Huang S, Cao Y, Yao Y, Li J, Chen J. YAP1 inhibits circRNA-000425 expression and thus promotes oncogenic activities of miR-17 and miR-106. Biochem Biophys Res Commun 2018;4:2370–75. [9] Liu H, Qiu Y, Pei X. Endothelial specific YY1 deletion restricts tumor angiogenesis and tumor growth. Sci Rep. 2020; 10. [10] Liu J ZX, Wang K, Zhang X, Yu Y, Lv Y, Zhang S, Zhang L, Guo Y, Li Y, Yang A, Zhang R, Li J. A novel YAP1/SLC35B4 regulatory axis contributes to proliferation and progression of gastric carcinoma. Cell Death Dis. 2019 Jun 7;10(6):452. doi: 10.1038/s41419-019-1674-2. PMID: 31175271; PMCID: PMC6555804. [11] Li X, Zhong, H., Shi, Q. et al. YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression. Cell. Mol. Life Sci. 81, 143 (2024). https://doi.org/10.1007/s00018-024-05178-3. [12] Wang W YY, Zhang RH, Deng JY, Sun Z, Seeruttun SR, Wang ZN, Xu HM, Liang H, Zhou ZW. Standardizing the classification of gastric cancer patients with limited and adequate number of retrieved lymph nodes: an externally validated approach using real-world data. Mil Med Res 2022; 9: 15 [RCA] [PMID: 35387671 DOI: 10.1186/s40779-022-00375-2] [FullText] [Full Text(PDF)]. [13] Gu YC, Li X, Zhao YJ, Wu T, Zhou CG, Hu WL, et al. Yin Yang 1-associated protein 1: Clinical significance and underlying functional mechanisms in gastric cancer. World J Gastroenterol 2026;32:URL: https://www.wjgnet.com/1007-9327/full/v32/i21/116527.htm DOI: https://dx.doi.org/10.3748/wjg.v32.i21.