Abstract
Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structural subunit and can form a heterodimer with IL-27p28 and IL-12p35 subunit to build IL-27 and IL-35, respectively. However, IL-27 stimulates whereas IL-35 inhibits antitumor T cell responses. To date, little is known about the role of EBI3 in tumor microenvironment. In this study, firstly we assessed EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of colorectal cancer (CRC) tissues; then we evaluated the antitumor T cell responses and tumor growth with a EBI3 blocking peptide. We found that elevated EBI3 may be associated with IL-12p35, gp130, and p-STAT3 to promote CRC progression. EBI3 blocking peptide promoted antitumor cytotoxic T lymphocyte (CTL) response by inducing Granzyme B, IFN-γ production, and p-STAT3 expression and inhibited CRC cell proliferation and tumor growth to associate with suppressing gp130 and p-STAT3 expression. Taken together, these results suggest that EBI3 may mediate a bidirectional reciprocal-regulation STAT3 signaling pathway to assist the tumor escape immune surveillance in CRC.
Highlights
The Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structurally homologous to the IL-12p40 subunit and forms a heterodimer either with the IL-27p28 subunit to build IL-27 or with IL-12p35 subunit to form IL-35
Our previously study demonstrated that overexpression of EBI3 and IL-12p35 promotes colorectal cancer (CRC) progression [13], the relationship of EBI3, IL-27p28, IL-12p35, gp130, and p-STAT3 expression with clinicopathological parameters of CRC has not previously been reported
We found that EBI3, IL-12p35, gp130, and p-STAT3 were highly expressed in all CRC sections to compare with the low or negative expression of IL-27p28 (Figure 1(a))
Summary
The Epstein-Barr virus-induced gene 3 (EBI3) is a member of the interleukin-12 (IL-12) family structurally homologous to the IL-12p40 subunit and forms a heterodimer either with the IL-27p28 subunit to build IL-27 or with IL-12p35 subunit to form IL-35. IL-35 appears to be produced mainly by regulatory T or B cells (Treg or Breg) and epithelial derived tumor cells with a protumor via expanding Tregs and inhibiting CD4+CD25− effector T cells [8], promoting IL-35-producing CD1dhighCD5+ B cells mediated tumor cell proliferation [9], enhancing myeloid cell accumulation [10], and inhibiting tumor cell apoptosis [11, 12]. Our previous reports found tumor-derived IL-35 or EBI3 associated with IL-12p35 may recruit Treg cells into the tumor microenvironment in favor of tumor growth in human colorectal cancer (CRC) [13]. The exact mechanisms of EBI3 in CRC tumor microenvironment are not fully understood
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