Tight junction proteins: Gatekeepers turned facilitators in the pathogenesis of gastric adenocarcinoma

Table 1 Dysregulated tight junction proteins and their mechanistic associations with gastric adenocarcinoma

No.	TJ proteins	Expression level in gastric carcinoma	Functional effect	Ref.
1	ZO	↓ ZO-1 and ZO-2, upregulated or downregulated	Loss of epithelial features. Induce EMT. Promote tumor invasion, metastasis and resistance to apoptosis	[31]
2	Occludins	Decreased expression	Wnt/β-catenin pathway activation. β-catenin pathway accumulation in cytoplasm, translocation to nucleus. Uncontrolled cell proliferation	[31]
3	Claudin 1	Increased	Increased claudin-1 → TJ hyperfunction → alters selective permeability of epithelium. Wnt/β-catenin pathway activation → uncontrolled cell proliferation, promotes EMT	[37]
4	Claudin 2	Increased	Increased intestinal permeability, activation of oncogenic signaling pathway, disruption of normal epithelial architecture, weakened cell-cell adhesion → metastasis	[37]
5	Claudin 3	Increased	Activation of inflammatory pathways (JAK/STAT, NF-κB) → immune invasion, promotes angiogenesis	[19]
6	Claudin 4	Decreased	Invasiveness, metastasis and tumor aggressiveness, poor survival	[31]
		Increased	Wnt/β-catenin pathway activation, PI3K/Akt signaling → enhances cell survival by promoting apoptosis and promotes EMT through TGF-β signaling. Promotes tumor-supportive microenvironment	[37]
7	Claudin 5	Increased	Suppresses apoptosis of gastric cells → uncontrolled proliferation of tumor cells	[38]
8	Claudin 6	Increased	Induces MMP-2 activation through claudin-1 membrane expression → promotes cell migration and invasiveness	[39]
9	Claudin 7	Increased	EMT → tumor invasion, aggression and metastasis	[19,40]
10	Claudin 12	Increased	Through the EMT, regulates apoptosis	[41]
11	Claudin 18	Decreased	Signaling cascade related to chemokines and Wnt signaling pathway	[42,43]
12	Claudin 23	Decreased	Recruits claudin 3, 4 and mediates through it	[44,45]

TJ: Tight junction; ZO: Zonula occludens; EMT: Epithelial mesenchymal transition; Wnt: Wingless related integration site; JAK: Janus kinase; STAT: Signal transducer and activator of transcription; NF-κB: Nuclear factor kappa B; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; TGF: Tissue growth factor; MMP-2: Matrix metalloproteinase 2.

Table 2 Claudin based immunotherapy for gastric cancer patients

No.	Targeted TJ proteins	Therapeutic agent(s)	Development stages in GC	Effect in GC patients	Ref.
1	Claudin 18.2 mAb	CMG901	Phase I	Demonstrated a manageable safety profile and promising antitumor activity	[93]
2	Claudin 18.2 mAb	IBI343	Phase I	Demonstrated a manageable safety profile with low gastrointestinal adverse events and showed promising efficacy	[94]
3	Claudin 18.2 mAb	CAR T-cell therapy, CT041	Phase II	Demonstrated significant improvement in progression-free survival, with a manageable safety profile	[95]
4	Claudin 18.2 mAb	Zolbetuximab plus mFOLFOX6	Phase III	Significantly prolonged progression-free survival and overall survival compared with placebo	[101]
5	Claudin 18.2 mAb	Zolbetuximab (IMAB362) combined with EOX	Phase II	Provided longer progression-free survival and overall survival compared with EOX alone. The primary endpoint was progression-free survival, while overall survival was assessed as a secondary endpoint	[102]
6	Claudin 18.2 mAb	Zolbetuximab	Phase I	Antitumor activity of IMAB362, both as a single agent and in combination with standard therapeutics, was observed	[103]
7	Claudin 18.2 mAb	Claudiximab	Phase II	Demonstrated significant efficacy and a favorable safety profile	[104]

TJ: Tight junction; GC: Gastric cancer; CAR: Chimeric antigen receptor; EOX: Epirubicin, oxaliplatin and capecitabine.