Letter to the Editor: Yin Yang 1 in inflammatory memory and progression susceptibility in Helicobacter pylori–associated gastric cancer

Abstract

Chen et al recently published a study in World Journal of Clinical Oncology, demonstrated that Helicobacter pylori induces Yin Yang 1 (YY1) expression and activates the Janus kinase 2-signal transducer and activator of transcriptional protein 3 pathway, thereby promoting epithelial–mesenchymal transition and gastric cancer progression. This commentary highlights how their findings refine the mechanistic understanding of a chronic infection–driven oncogenic cascade and positions YY1 as a central regulator linking inflammatory stimulation with malignant evolution. When considered within the broader framework of inflammatory memory and epigenetic imprinting, the sustained upregulation of YY1 across precancerous stages suggests that YY1 may function as a molecular imprint of chronic injury and a determinant of individual susceptibility to disease progression.

Key Words: Helicobacter pylori; Gastric cancer; Yin Yang 1; Janus kinase 2-signal transducer and activator of transcriptional protein 3 signaling; Epithelial–mesenchymal transition; Inflammatory memory; Progression susceptibility; Epigenetic imprinting

Core Tip: This commentary discusses the study by Chen et al, which demonstrated that Yin Yang 1 (YY1) mediates Helicobacter pylori (H. pylori)-induced activation of the Janus kinase 2-signal transducer and activator of transcriptional protein 3 pathway and epithelial–mesenchymal transition in gastric cancer. By integrating recent work on innate and epithelial inflammatory memory with the broader biology of YY1 in malignancy, this article proposes that sustained and heterogeneous upregulation of YY1 may represent an inflammation-derived transcriptional imprint and an early determinant of susceptibility to disease progression. These insights open new directions for risk stratification and pathway-targeted prevention in H. pylori-infected individuals.

TO THE EDITOR

We read with great interest the recent study published in World Journal of Clinical Oncology by Chen et al[1], which delineates how Helicobacter pylori (H. pylori) induces the transcription factor Yin Yang 1 (YY1) and activates the Janus kinase 2-signal transducer and activator of transcriptional protein 3 (JAK2/STAT3) pathway to drive epithelial–mesenchymal transition (EMT) and malignant progression in gastric cancer. By integrating patient tissues, in vitro infection models, and mouse studies, the authors constructed a coherent mechanistic axis linking chronic inflammatory stimulation to transcriptional reprogramming and invasive tumor behavior. Their work provides a valuable framework for understanding how persistent infection promotes a protumorigenic microenvironment and places YY1 at a critical crossroads of inflammation and carcinogenesis (Figure 1).

Figure 1 Schematic of the core hypothesis. Heterogeneous Yin Yang 1 expression mediates inflammatory imprinting and bifurcated susceptibility to gastric cancer progression in Helicobacter pylori infection. TNF: Tumor necrosis factor; IL: Interleukin; YY1: Yin Yang 1; EMT: Epithelial–mesenchymal transition; JAK2/STAT3: Janus kinase 2-signal transducer and activator of transcriptional protein 3.

YY1 as a transcriptional imprint of inflammatory memory

One of the most compelling observations is the early and sustained elevation of YY1 in gastritis, intestinal metaplasia, and cancer. Rather than representing a short-lived response to bacterial exposure, this pattern suggests a persistent transcriptional state that accompanies the Correa cascade. The concept of such persistence aligns closely with recent advances in “inflammatory memory.” Studies in myeloid cells have demonstrated that exposure to allergens or microbial cues can imprint a tumor necrosis factor-dependent inflammatory memory[2]. Similarly, epithelial and tissue stem cells can acquire long-lasting metabolic and epigenetic scars after inflammatory episodes, altering their behavior during subsequent challenges[3,4]. When viewed through this lens, the progressive upregulation of YY1 described by Chen et al[1] may represent a mucosal transcriptional imprint derived from chronic H. pylori-induced injury rather than a simple marker of active infection.

Heterogeneity and progression susceptibility

Importantly, the authors report substantial heterogeneity in YY1 expression among H. pylori-infected individuals, even within the same histologic stage. This divergence resonates with the broader theory that inflammatory imprinting varies among individuals and may underlie why only a minority of infected hosts develop gastric cancer despite the high global prevalence of H. pylori. Early differences in the magnitude or stability of YY1 induction could constitute a molecular branching point that determines susceptibility to disease progression. This interpretation is consistent with prior work showing that epigenetic imprinting in intestinal stem cells can durably modify regenerative trajectories and vulnerability to future insults[4].

YY1 as a central transcription hub

The broader cancer biology literature supports the notion that YY1 has the biochemical capabilities required to stabilize persistent transcriptional states. YY1 modulates immune resistance by regulating programmed death-ligand 1 expression[5], can be post-translationally stabilized by ubiquitin-specific-processing protease 7 to maintain oncogenic transcription and metastatic behavior[6], and participates in an EZH2-RKIP epigenetic axis that reinforces immune evasion and chronic inflammation[7]. Together, these properties suggest that YY1 is not merely a downstream responder but rather a transcriptional hub capable of sustaining protumorigenic signaling. Within this framework, the YY1-JAK2/STAT3-EMT pathway reported by Chen et al[1] may represent a specific manifestation of a durable inflammation-derived transcriptional program.

Future directions and therapeutic implications

Several future directions emerge from integrating these findings with current concepts of inflammatory memory. First, defining the mechanisms that preserve YY1 activation during chronic infection—including feedback circuits and epigenetic stabilization—will clarify whether YY1 represents a reversible or entrenched state. Second, prospective evaluation of YY1 expression divergence in H. pylori-infected cohorts may determine its utility for risk stratification across gastritis and intestinal metaplasia. Third, investigating whether modulation of YY1 or JAK2/STAT3 can suppress EMT and reshape local immunity could inform pathway-targeted interception strategies. Ultimately, determining whether YY1 acts primarily as a driver or as an amplifier of inflammatory signaling will influence whether it should be viewed as a therapeutic target, a biomarker, or both.

CONCLUSION

Chen et al[1] provide compelling evidence that YY1 links H. pylori-induced inflammation to JAK2/STAT3 activation, EMT, and gastric cancer progression. When contextualized within emerging frameworks of inflammatory memory and epigenetic imprinting[2], their findings raise the possibility that YY1 functions as a molecular imprint of chronic injury and a determinant of susceptibility to disease progression. Further elucidation of how this YY1-associated state is established, maintained, and potentially reversed may open new avenues for risk prediction and targeted prevention in H. pylori-associated gastric cancer.