14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules

Abstract

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.

Molecular carcinogenesis in equine penile cancer: A potential animal model for human penile cancer

“…Recently stromal expression of 14-3-3σ has been demonstrated in endometrial carcinomas and, similar to our results, the neoexpression by fibroblasts in areas of desmoplasia at the IF could be indicative of an active proinvasive environment within the extracellular matrix [40]. To provide more evidence of the role of 14-3-3σ in cancer development, recently it has been shown that 14-3-3σ provides chemoresistance properties to SCC and this fact, along with the anti-apoptotic properties of 14-3-3σ in tumoral cells, highlights the potential of this protein as a very promising biomarker and therapeutic target for penile SCC [18,[41][42][43].…”

“…E-cadherin and vimentin are proteins associated with the epithelial-mesenchymal transition (EMT) process, which have been associated with a poorer prognosis [13,14]. Additionally, 14-3-3σ is an oncoprotein that promotes cell proliferation, survival, invasiveness, metastasis and chemoresistance by binding and modulating various molecular pathways in vulvar, cervical and head and neck SCC [15][16][17][18].…”

iTRAQ-based quantitative proteomic analysis of differentially expressed proteins in chemoresistant nasopharyngeal carcinoma

“…[57][58][59][60][61] Many studies have reported that 14-3-3 sigma is closely related to tumor resistance. [62][63][64][65][66] In our preliminary study, SFN was highly expressed in CNE2DDP cells, which is the basis of our follow-up study.…”

ECRG2 enhances the anti-cancer effects of cisplatin in cisplatin-resistant esophageal cancer cells via upregulation of p53 and downregulation of PNCA

“…Lee et al[12] reported that the novel oxygen carrier YQ23 enhanced the DDP response of chemoresistant esophageal tumor xenografts, as well as reducing tumor size and the number of animals with invasive tumors. Lai et al[13] provided evidence that 14-3-3σ, or its related DNA repair molecule, is a promising therapeutic target for counteracting DDP resistance in esophageal squamous cell carcinoma. Furthermore, Yu et al[14] suggested autophagy is a novel target to improve the efficiency of DDP in human esophageal cancers with acquired resistance.…”