REG3β Plays a Key Role in IL17RA Protumoral Effect—Letter

Abstract

We have read with great interest the recent report by Loncle and colleagues (1) investigating the role of REG3b in mediating protumoral effects of IL17. We agree in principal with their conclusion that Reg3b is involved in the initiation of pancreatic ductal adenocarcinoma (PDAC) and its progression. We also found Reg gene expression in duct-like structures in tumor-adjacent areas of pancreatic cancer in our study (article submitted to Modern Pathology, MP-2015MP- -1066, which is an indicator of acinar-to-ductal metaplasia as described in this article. However, we would like to clarify two potential controversies. First, the results of Fig. 5B showing Reg3b expression in human peritumor and well-differentiated PDAC lesions are questionable because Reg3b (transcript ID NM_011036) is only expressed in rodents; its human ortholog is Reg3A (NM_002580.2; ref. 2). They share the name of pancreatitis-associated protein and are both expressed after pancreatitis and in normal intestine (3). The result obtained on human tissues by using mouse Reg3b antibody (Dynabio S.A.) is very different from what we have seen using human Reg3A antibody (sc-134854, against residues 107-175). In short, we have never seen significant staining of Reg3A in either well-or poorly differentiated cancer cells. Instead, it is highly expressed in stromal cells surrounding the cancer epithelium, which was not described in the article.Second, the authors used a gp130 antibody to block the action of Reg3b. However, the designation of Reg3b receptor gp130 (glycoprotein 130) has not been reported. There has never been a consensus on a cell surface receptor activated by either mouse Reg3b or human Reg3A, nor a peer-reviewed evidence showing receptor binding, competitive, or functional blockage. Only a review article has predicted that Reg3b expression might be stimulated by ciliary neurotrophic factor-related cytokines through the leukemia inhibitory factor (LIF) receptor complex, including gp130 and LIF receptor b (4). Thus, the use of gp130 antibody does not support the involvement of Reg3b in STAT3 phosphorylation and cell proliferation. This claim would mislead the readers. For all Reg proteins (7 in rodents and 5 in human), only a receptor for Reg1 (exostosin-like 3, EXTL3) has been reported and confirmed (5). Related to this potential defect, we do not believe that the proposed gp130-JAK2-STAT3 signaling pathway has been well established.Despite these disagreements, we still feel that this is an excellent article that opens up a new prospect on the treatment and prevention of pancreatic cancer. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.Received October 23, 2015; revised December 19, 2015; accepted December 29, 2015; published OnlineFirst March 18, 2016. 3. Itoh T, Teraoka H. Cloning and tissue-specific expression of cDNAs for the human and mouse homologues of rat pancreatitis-associated protein (PAP).

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

“…Neutralization with antibodies for Reg3b or IL17A inhibits PanIN development in Pdx1-Cre; Kras G 12 D ; Reg3b +/+ mice. Reg3b signals through the gp130-JAK2-STAT3 axis promoting cell growth and resistance to apoptosis based on the decline in the number of Reg3b + cells from the peritumoral region to PDAC lesions exhibiting poorly differentiated cells [although the pattern of Reg3b in this report was debated (Li et al, 2016a; Loncle et al, 2016)]. Along the same lines, REG3A was linked to the activation of the JAK2-STAT3 pathway in pancreatic cancer cell lines (Liu et al, 2015) and of the MAPK in acinar cells (Ferres-Maso et al, 2009).…”