HAb18G/CD147 Promotes pSTAT3-Mediated Pancreatic Cancer Development via CD44s

Abstract

Purpose STAT3 plays a critical role in initiation and progression of pancreatic cancer. However, therapeutically targeting STAT3 is failure in clinic. We previously identified HAb18G/CD147 as an effective target for cancer treatment. In this study, we aimed to investigate potential role of HAb18G/CD147 in STAT3-involved pancreatic tumorigenesis in vitro and in vivo. Experimental Design The expression of HAb18G/CD147, pSTAT3 and CD44s were determined in tissue microarrays. The tumorigenic function and molecular signaling mechanism of HAb18G/CD147 was assessed by in vitro cellular and clonogenic growth, reporter assay, immunoblot, immunofluorescence staining, immunoprecipitation, and in vivo tumor formationusing loss or gain-of-function strategies. Results Highly expressed HAb18G/CD147 promoted cellular and clonogenic growth in vitro and tumorigenicity in vivo. CyPA, a ligand of CD147, stimulated STAT3 phosphorylation and its downstream genes cyclin D1/survivin through HAb18G/CD147 dependent mechanisms. HAb18G/CD147 was associated and co-localized with cancer stem cell marker CD44s in lipid rafts. The inhibitors of STAT3 and survivin, as well as CD44s neutralizing antibodies suppressed the HAb18G/CD147-induced cell growth. High HAb18G/CD147 expression in pancreatic cancer was significantly correlated with the poor tumor differentiation, and the high co-expression of HAb18G/CD147-CD44s-STAT3 associated with poor survival of patients with pancreatic cancer. Conclusions We identified HAb18G/CD147 as a novel upstream activator of STAT3 via interacts with CD44s and plays a critical role in the development of pancreatic cancer. The data suggest HAb18G/CD147 could be a promising therapeutic target for highly aggressive pancreatic cancer and a surrogate marker in the STAT3-targeted molecular therapies.

Antibody Against CD44s Inhibits Pancreatic Tumor Initiation and Postradiation Recurrence in Mice

“…As shown in Figure 5E, FLLL32, a specific STAT3 inhibitor 26, 28 that moderately inhibits tumorsphere formation alone, significantly enhanced the H4C4-induced tumorsphere inhibition, from 40.8 ± 0.009% inhibition by H4C4 alone to 60.3 ± 0.021% inhibition when combined with H4C4 ( P < 0.001). Similarly, the specific survivin inhibitor YM155 also enhanced H4C4-mediated tumorsphere inhibition ( P < 0.001).…”

“…We observed that CD44s was highly expressed in PANC-1, MIA PaCa-2, AsPC-1 and HS-766T cell lines, as well as in human pancreatic cancer primary tumor early passage xenograft, J-2 (Figure 1D–E). Based on this result and our previous observation 11, 26 that PANC-1 and MIA PaCa-2 are highly tumorigenic in vivo and reproducibly form tumorspheres in vitro , these two cell lines as well as early passage xenograft, J-2, were selected for the current study.…”

“…Anti-human CD44s monoclonal antibody was prepared by our lab from hybridoma H4C4 (University of Iowa Developmental Studies Hybridoma Bank) [1]. FLLL32 was a kind gift from Dr. Jiayuh Lin as previously described [2, 3]. …”

“…At the time of diagnosis, over 80% of the patients are not eligible for curative surgery resection and 70–80% of patients die with widespread metastatic disease 2 . Patients with locally advanced (unresectable) disease treated with chemoradiation have a median survival time of only 10–12 months due to both local disease progression and metastasis 3, 4 . Therfore, it is critical to develop new therapeutic strategies based on a new understanding of the biological mechanisms of resistance and recurrence.…”

Cyclophilin function in Cancer; lessons from virus replication

“…Thus, it is proposed that by its interaction with STAT3, CypD can regulate the G1 to S phase transition. Furthermore, recent work has demonstrated that CypA stimulates phosphorylation of STAT3 and transcription of cyclin D1/surviving [107].…”