Abstract
Laryngeal squamous cell carcinoma (LSCC) is one of the most common carcinomas of the head and neck. Despite advances in diagnosis and treatment, the survival of patients with LSCC has not improved in the past two decades. TIP30, a newly identified tumour suppressor, appears to be involved in multiple processes during tumour development. Here, we investigated the involvement of TIP30 in chemoresistance of LSCC in vitro and in vivo. We showed that TIP30 expression decreased significantly in drug-selected cells (DSCs) of laryngeal carcinoma. Suppressing TIP30 enhanced resistance capability to multiple chemotherapy drugs, cell proliferation and self-renewal in Hep2 cells. Additionally, decreased self-renewal capacity and chemotherapeutic resistance were observed in DSCs overexpressing TIP30. Furthermore, TIP30 negatively regulated tumourigenesis and chemoresistance in LSCC cells subcutaneously transplanted into nude mice. Moreover, decreased TIP30 expression contributed to chemoresistance, self-renewal and proliferation of LSCC cells via nuclearlisation of β-catenin, a cell–cell adhesion and stem cell renewal regulator. Consistently, Kaplan–Meier and Cox proportional hazards regression modelling analyses showed that decreased TIP30 expression independently predicted poor survival in patients with LSCC. Taken together, our results reveal that TIP30 has a crucial role in chemoresistance of LSCC through the AKT/glycogen synthase kinase-3β/β-catenin signalling pathway and may be a promising candidate for improving LSCC chemotherapy.
Highlights
A major obstacle in cancer treatment is the development of multidrug resistance
TIP30 is positively expressed in many normal human tissues but decreased expression is observed in some tumour tissues such as melanoma, breast cancer, neuroblastoma, glioblastoma, colon cancer and hepatocellular carcinoma (HCC).[14,15,16,17]
Our previous studies revealed that decreased TIP30 expression induces the epithelial–mesenchymal transition (EMT), a process related to tumour stemness, including selfrenewal and chemotherapeutic resistance[21] in pancreatic cancer cells.[22]
Summary
A major obstacle in cancer treatment is the development of multidrug resistance. Drug-selected cells (DSCs) have been established to further explore the mechanism of multichemoresistance. The properties of DSCs include multidrug resistance[6] and a stem-like phenotype,[7] characterised by enhanced tumour initiation,[8,9] metastasis[10] and recurrence.[11,12,13]. Forced expression of TIP30 sensitises HCC cells to 5-flurouracil (5-FU) and significantly inhibits growth of HCC xenografts in mice when combined with 5-FU.[18] Our previous studies revealed that decreased TIP30 expression induces the epithelial–mesenchymal transition (EMT), a process related to tumour stemness, including selfrenewal and chemotherapeutic resistance[21] in pancreatic cancer cells.[22] sorafenib, an angiogenesis. Forced expression of TIP30 greatly enhanced chemotherapeutic sensitivity of LSCC cells and prolonged survival of LSCC-xenografted mice. Our results suggest that decreased TIP30 expression enhanced chemotherapeutic resistance and self-renewal abilities of LSCC cells by modulating nuclearlisation of β-catenin. We further investigated the correlation between TIP30 expression and clinicopathologic characteristics and revealed its prognostic potential in patients with LSCC
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