Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer

Abstract

The signal-transcriptional factor signal transducer and activator of transcription (STAT3) is overexpressed in various tumor entities and promotes tumor progression and metastasis. The tyrosine-kinase receptor Her-2 was shown to activate STAT3-expression and is overexpressed in a subtype of esophageal cancer (EC). STAT3 also regulates carbonic anhydrase IX (CAIX) expression in vivo, promoting IL-6-dependent tumor invasion.Tumor-tissue from 324 patients with EC and 45 patients with precursor lesions were analyzed for the expressions of tyrosine-705 phosphorylated STAT3 (pSTAT3). Data on Her-2-status and CAIX expression were available from previous studies. pSTAT3 was overexpressed in 40 % of adenocarcinomas (AC) and 50 % of squamous cell carcinomas of the esophagus and was associated with worse overall (OS) (p = 0.001) and disease free survival (DFS) (p = 0.001). In Barrett's mucosa without/low-grade dysplasia, pSTAT3 was expressed in 14 % compared to 27 % in patients with high-grade dysplasia (p = 0.018). A significant association between Her-2 and pSTAT3 was found in ACs (p = 0.013), showing that patients with tumors expressing both proteins have significantly worse OS (p = 0.0039) and DFS (p = 0.029). One hundred-fifty (46.3 %) cancer cases were considered as positive for CAIX expression, and a strong correlation between pSTAT3 and CAIX expression was seen (p < 0.001). pSTAT3 plays an important role in the development of AC. Expression of pSTAT3 correlates with Her-2 status and CAIX expression and is associated with tumor progression and worse outcome, offering expectantly therapeutical implications.

Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use

“…Furthermore, CA IX expression correlates with various prognostic factors, including c-ErbB2 [124,125], epidermal growth factor receptor, c-ErbB2 and MUC-1 [126], EGFR and matrix metalloproteinase MMP-9 [102], osteopontin and CD44 [127], p53 and p300 [128], estrogen receptor, progesterone receptor, bcl-2, p53, c-ErbB2 and Ki-67 [114], cyclin E, cyclin A2, Ki-67 [111], lysyl oxidase, ephrin A1, galectin-1 [117], Slug [51], manganese superoxide dismutase [129], etc. Elevated CA IX protein in triple-negative breast cancer is associated with a BRCA1 mutant signature and loss of BRCA1 function [53].…”

The Role of STAT3 in Thyroid Cancer

“…It has been shown that upregulated expression of STAT3 is associated with more malignant behavior of tumor cells and worse prognosis in a variety of human malignancies, e.g., cancers of the breast, prostate, ovary, lung, head and neck, esophagus, and brain [53,54,55,56,57,58,59,60,61]. In pancreatic cancer, STAT3 was shown to regulate angiogenesis and metastasis [62] and to promote cellular proliferation by accelerating G1/S-phase progression [63].…”

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

“…CA9 was reported to be an endogenous sensor to HIF-1 activity (27) and CA9 inhibitors were more potent in 3D culture due to the regions of hypoxia (28). One report demonstrated a strong correlation in vivo between pSTAT3 and CA9 expression and postulated that the regulation of CA9 by STAT3 could be important in invasion through IL-6 signaling (29). Both of these transcription factors are regulated by APE1/Ref-1, so the impact of APE1/Ref-1 redox activity on HIF1 activity as well as CA9 expression was evaluated in PDAC following exposure to hypoxia.…”