PAI1 is a Marker of Bad Prognosis in Rectal Cancer but Predicts a Better Response to Treatment with PIM Inhibitor AZD1208

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide. The standard treatment in locally advanced rectal cancer is preoperative radiation alone or in combination with chemotherapy, followed by adjuvant chemotherapy. Rectal cancer is highly lethal, with only 20% of patients showing a complete remission (by RECIST) after standard treatment, although they commonly show local or systemic relapse likely due to its late detection and high chemotherapy resistance, among other reasons. Here, we explored the role of PAI1 (Serpin E1) in rectal cancer through the analyses of public patient databases, our own cohort of locally advanced rectal cancer patients and a panel of CRC cell lines. We showed that PAI1 expression is upregulated in rectal tumors, which is associated with decreased overall survival and increased metastasis and invasion in advanced rectal tumors. Accordingly, PAI1 expression is correlated with the expression of (Epithelial-to-Mesenchymal Transition) EMT-associated genes and genes encoding drug targets, including the tyrosine kinases PDGFRb, PDGFRa and FYN, the serine/threonine kinase PIM1 and BRAF. In addition, we demonstrate that cells expressing PAI1 protein are more sensitive to the PIM inhibitor AZD1208, suggesting that PAI1 could be used to predict response to treatment with PIM inhibitors and to complement radiotherapy in rectal tumors.

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

“…Accumulating evidence has suggested that PAI-1 contributed to tumor cell proliferation, migration, invasion, drug resistance and epithelial-mesenchymal transition (EMT), and that high PAI-1 protein expression was associated with unfavorable biological behavior and patient prognosis in HCC ( 19 , 21 , 22 ). Therefore, the present study selected PAI-1 for subsequent functional analysis and investigated the roles of PAI-1 in TAM(CAF).…”

“…Our previous study revealed that lactate secreted by HCC and PDAC cells stimulated the M2 phenotypic transformation of macrophages and enhanced VEGF expression by nuclear factor erythroid 2-related factor 2 (NRF2) activation, and that M2 macrophages triggered NRF2 signaling activation in cancer cells via paracrine VEGF, thereby promoting EMT ( 6 ). Several previous studies have shown that PAI-1 contributed to cell invasion and migration by mediating EMT in colorectal cancer ( 19 ), gastric adenocarcinoma ( 48 ) and non-small cell lung cancer ( 49 ). Furthermore, the present results demonstrated that E-cadherin protein expression level was downregulated, while N-cadherin, Snail and Twist1 protein expression levels were upregulated in the Huh-7 treated with TAM(CAF), and these effects were reversed by the inhibition of PAI-1.…”

“…Furthermore, SK-216 exerted an anti-tumor effect by reducing tumor size and inhibiting angiogenesis and metastasis in mice with lung carcinoma and melanoma ( 52 ). However, the short effective half-life of these inhibitors in the body has limited their clinical use, as sufficient concentrations are often difficult to achieve, particularly in the tumor area, during long-term cancer treatment ( 19 ). Therefore, anti-PAI-1 therapy in cancer treatment remains a promising but challenging strategy, and the development of more effective and safe inhibitors is required.…”

“…Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor encoded by the serpin family E member 1 gene ( 16 ). PAI-1 was found to be upregulated in a variety of different tumors, such as breast ( 17 ), ovarian ( 18 ) and colon cancers ( 19 ), and possess several pro-tumorigenic functions, including supporting proliferation and angiogenesis, inhibiting cell apoptosis and promoting metastasis ( 17 , 18 , 20 ). Along with cancer cells, several other components of the TME, including platelets, macrophages and vascular cells, also secrete PAI-1 ( 16 , 21 ).…”

Single‐cell RNA sequencing reveals SERPINE1‐expressing CAFs remodelling tumour microenvironment in recurrent osteosarcoma

“…SERPINE1 has been widely known to regulate the progression of numerous cancers, which highlights the application of SERPINE1 as a potential target. 9,10 We validated that SERPINE1 was remarkably correlated with macrophage infiltrations and the EMT of OS. Knocking down SERPINE1 by si-SERPINE1 could decrease CAFs infiltration and activity, and inhibit OS progression via inducing M1 macrophage polarisation (Figure 4).…”