SERPINB2 down‐regulation contributes to chemoresistance in head and neck cancer

Abstract

Resistance to cisplatin-based chemotherapy is responsible for the majority of deaths from head and neck squamous cell carcinoma (HNSCC). In this study, using genome-wide gene expression analysis to investigate potential molecular mediators of HNSCC chemoresistance, we identified SERPINB2, a known inhibitor of extracellular serine proteinase urokinase-type plasminogen activator (uPA), as an important candidate. Whereas SERPINB2 is known to function as a suppressor of uPA molecular cascades, many of which play important roles in tumor invasion and metastasis, a role for SERPINB2 in cancer drug resistance has not been examined. By using quantitative real-time PCR and Western blot analysis, we determined that SERPINB2 mRNA and protein levels correlated with chemoresistance in HNSCC cell lines, and significantly lower SERPINB2 expression levels were observed in two cisplatin resistant HNSCC subclones compared to their isogenic drug-sensitive parental lines. Immunohistochemical analysis of HNSCC tumor tissues from patients treated with neoadjuvant cisplatin-based chemotherapy (n = 67 cases) revealed a significant association between SERPINB2 protein levels, tumor differentiation and patient relapse. Moreover, SERPINB2 down-regulation was a strong predictor of reduced overall survival in patients with HNSCC who received cisplatin-based chemotherapy (P = 0.001, log rank test). Studies using either siRNA-mediated down-regulation or forced over-expression of SERPINB2 in HNSCC cell lines confirmed a functional role for SERPINB2 in drug resistance. The findings were further supported using chemical inhibitors of STAT3 activity (a downstream effecter of uPAR signaling pathway), showing that STAT3 suppression altered HNSCC cell line cisplatin sensitivity. This is the first report on a role for SERPINB2 in acquired resistance to cisplatin in patients with HNSCC.

NO•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer

“…Similarly, cytokines including IL‐1b , IL‐6 and IL‐8 are implicated in tumorigenesis and their increased expression is associated with the development, progression and therapeutic resistance in pancreatic cancer . The role of SERPINB2 , which encodes the plasminogen activator inhibitor 2, is context‐dependent in cancer and both tumor‐suppressing and promoting functions are reported . However, a potential tumor‐suppressive role of SERPINB2 is earlier described in pancreatic cancer .…”

“…[30][31][32][33][34][35] The role of SERPINB2, which encodes the plasminogen activator inhibitor 2, is contextdependent in cancer and both tumor-suppressing and promoting functions are reported. 36,37 However, a potential tumorsuppressive role of SERPINB2 is earlier described in pancreatic cancer. 38 Therefore, the significance of SERPINB2 in the context of NO • /Kynurenine/AHR mediated signaling in pancreatic cancer needs further clarification.…”

A new long noncoding RNA (lncRNA) is induced in cutaneous squamous cell carcinoma and down-regulates several anticancer and cell differentiation genes in mouse

“…Finally, clinical results reveal that a lower level of SERPINB2 expression is associated with poor prognosis and outcome in head and neck, gastric, breast, and lung cancers (53)(54)(55). In contrast, overexpression of SERPINB2 was found to result in suppression of invasion of cancer cells (56,57).…”

Down-regulation of SerpinB2 is associated with gefitinib resistance in non-small cell lung cancer and enhances invadopodia-like structure protrusions

“…In contrast, decreased SerpinB2 levels have been correlated with unfavourable outcomes in breast18, head and neck19, gastric20 and liver21 cancers. Moreover, a recent study reported that the down-regulation of SerpinB2 is associated with an acquired resistance to cisplatin in head and neck squamous cell cancer22.…”