Interleukins 4 and 13 and Their Receptors Are Differently Expressed in Gastrointestinal Tract Cancers, Depending on the Anatomical Site and Disease Advancement, and Improve Colon Cancer Cell Viability and Motility

Abstract

Immunosuppressive interleukins (IL)-4 and 13 may directly promote cancer but neither their status nor role in gastrointestinal tract is clarified. We aim at quantifying ILs and their receptors in paired normal-tumor samples (n = 49/51) and sera (n = 263), using immunoassays and RTqPCR, and screening for their effect on colonic cancer cells. Both ILs were elevated locally at protein level in all cancers but only IL13 transcripts in colon were upregulated. Interleukin and their receptor expression reflected cancer pathology to varying degrees, with the association frequently inverse and manifested in non-cancerous tissue. Positive correlation with cancer-promoting genes BCL2, BCLxL, HIF1A, VEGFA, ACTA2, CCL2, PTGS2, and CDKN1A, but not Ki67, was demonstrated, particularly for ILs’ receptors. Circulating IL-4 was elevated in all, while IL-13 only in colorectal or esophageal cancers, reflecting their advancement. IL4Ra and IL13Ra1 transcripts were downregulated by hypoxia and, in Caco-2, also by IL-4. Interleukin stimulation slightly improved colonic cancer cell viability, weakly upregulating BCL2 and Ki67 in HCT116 and HT-29. It affected cell motility more markedly and was consistently accompanied by upregulation of claudin-2. Gastrointestinal tract cancers are associated with IL-4 and IL-13 upregulation, which may facilitate cancer growth. Targeting both interleukins as an antineoplastic strategy warrants further investigation.

Distinct Local and Systemic Molecular Signatures in the Esophageal and Gastric Cancers: Possible Therapy Targets and Biomarkers for Gastric Cancer

“…We further observed that non-cancerous gastric mucosa expressed markedly more pro-angiogenic factors ( HIF1A , VEGFA , and IL7 and its receptor IL7Ra ) and EMT markers ( CLDN2 , ACTA2 , and TJP1 ). Those observations add to the growing awareness that the macroscopically normal tumor-surrounding tissue might harbor molecular alterations [ 9 , 12 , 13 , 14 , 15 , 16 ]. Although not sufficient to change cell morphology, they are still of clinical relevance as the phenomenon of “molecular margin” is being argued to contribute to therapy failure and cancer recurrence following curative resection and/or to the occurrence of synchronous multiple tumors [ 12 , 13 ].…”

“…Claudin-2 is a pore forming protein but mounting evidence suggests that its role is not limited to regulating epithelial barrier permeability. The bulk of existing studies on claudin-2 in the gastrointestinal tract concerns colorectal cancer, where it is upregulated in response to IL-4 and IL-13 [ 16 ] and involved in promoting proliferation, survival, migration, colony formation, and drug resistance [ 16 , 36 , 37 ]. In addition, claudin-2 has been shown to facilitate self-renewal of colorectal stem-like cells.…”

Local and Systemic Interleukin-32 in Esophageal, Gastric, and Colorectal Cancers: Clinical and Diagnostic Significance

“…As mentioned earlier, it may result from applied antibody being not optimal but may also indicate a cancer-associated accumulation of the interleukin in tumor-adjacent tissue. As has been repeatedly demonstrated [ 22 , 23 , 36 , 37 , 38 ], alterations in molecular profile of still non-transformed cells in tumor vicinity are common and may precede morphological and histological changes. The “tumor molecular margin” phenomenon predispose to neoplastic transformation and accounts for cancer recurrence and the synchronous tumors [ 39 , 40 , 41 ].…”

“…Data on relative expression of IL4 , IL4Ra , IL7 , IL7Ra , IL10 , IL10Ra , IL13 , IL13Ra , ACTA2 , BCL2 , BCLxL , CCL2 , CDKN1A , CLDN2 , SLC2A1 , HIF1A , Ki67 , NOS2 , ODC1 , PTGS2 , TJP1 , and VEGFA in tissue samples investigated were available for 45 cancer patients and were retrieved from our earlier studies [ 22 , 23 ] for the purpose of correlation analysis.…”

Simultaneous LC-MS/MS-Based Quantification of Free 3-Nitro-l-tyrosine, 3-Chloro-l-tyrosine, and 3-Bromo-l-tyrosine in Plasma of Colorectal Cancer Patients during Early Postoperative Period

“…Moreover, while the oxidative stress is clearly pro-tumorigenic in early stages of neoplastic transformation, the excessive production of oxygen and nitrogen radicals at later stages may become disadvantageous, causing destabilization of the tumor cell genome and promoting cell senescence and death [2,47]. Furthermore, the immunosuppressive environment and its key mediators, including IL-4 and IL-13, elevated in CRC [48], inhibit NOS2 expression in macrophages [49]. Interestingly, only the concentration of 3-CT tended to increase with CRC advancement.…”