SCCA1/SERPINB3 Promotes Oncogenesis and Epithelial–Mesenchymal Transition via the Unfolded Protein Response and IL6 Signaling

Abstract

The serine/cysteine protease inhibitor SCCA1 (Serpin B3) is upregulated in many advanced cancers with poor prognosis, but there is limited information about whether it makes functional contributions to malignancy. Here we show that SCCA1 expression promoted oncogenic transformation and epithelial-mesenchymal transition (EMT) in mammary epithelial cells, and that SCCA1 silencing in breast cancer cells halted their proliferation. SCCA1 overexpression in neu+ mammary tumors increased the unfolded protein response (UPR), IL-6 expression, and inflammatory phenotypes. Mechanistically, SCCA1 induced a prolonged non-lethal increase in the UPR that was sufficient to activate NF-κB and expression of the pro-tumorigenic cytokine IL-6. Overall, our findings established that SCCA1 contributes to tumorigenesis by promoting EMT and a UPR-dependent induction of NF-κB and IL-6 autocrine signaling that promotes a pro-tumorigenic inflammation.

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…In addition, PI3K/Akt showed higher activity and integrin-linked kinase (ILK) exhibit in the mesenchymal cells as compared to epithelial cells [70,71]. Many pathways and molecules involved in these pathways play a crucial role in regulation, induction and reversion of EMT, including Wnt, TGFβ, RTK and other signaling pathways [72][73][74][75][76][77][78][79][80][81]. The detailed information was depicted in Table 1.…”

SERPINB3 and B4: From biochemistry to biology

“…Ectopic expression of SERPINB3 leads to oncogenic transformation of the non-tumorigenic mammary epithelial MCF10A cells [79]. Suppression of SERPINB3 using antisense RNA or short-hairpin RNA leads to decreased growth of a SCC cell line and a number of breast and pancreatic cancer cells [43, 79, 80]. A well characterized oncogenic feature of SERPINB3/B4 is the induction of epithelial-mesenchymal transition (EMT).…”

Signaling the Unfolded Protein Response in primary brain cancers

“…Indeed UPR involvement in EMT was recently shown in breast cancers (Del Vecchio et al, 2014;Feng et al, 2014;Ulianich et al, 2008). In mammary epithelial cells, overexpression of Serpin B3, a serine/cysteine protease inhibitor, induces chronic UPR that in turn activates NF-κB and leads to IL-6 production, thus resulting in an EMT-like phenotype (Sheshadri et al, 2014). EMT is also associated with an important change in ECM architecture, allowing tumor cell invasion.…”