HSPA5 overexpression predicts poor prognosis and drives radioresistance and metastasis in nasopharyngeal carcinoma.

objectiveThis study aimed to determine HSPA5 expression in NPC, evaluate its prognostic significance in patients receiving radiotherapy, and validate these findings in vitro.

methodsIn 107 NPC patients, the association between HSPA5 expression and clinicopathological characteristics was assessed using the chi-square test. All tumor specimens were collected before radiotherapy and were pathologically confirmed as poorly differentiated or undifferentiated without distant metastasis. All patients subsequently underwent radiotherapy and were followed for survival outcomes. In vitro, an HSPA5-knockout C666-1R cell line (C666-1R KO) was generated using CRISPR/Cas9, whereas HSPA5 overexpression in radiosensitive C666-1 cells (C666-1 OE) was established by transfection with the pcDNA3.1(+)-HSPA5 plasmid. The effects of HSPA5 expression on post-irradiation clonogenic survival, migration, and invasion were evaluated.

resultsIn NPC, HSPA5 expression was associated with gender, recurrence, distant metastasis, disease progression and radiosensitivity, but not with age, Histologic pattern, clinical stage, T stage, or N stage. High HSPA5 expression was detected in 47 NPC specimens. Kaplan–Meier analysis showed that, compared with the low-expression group, patients with high HSPA5 expression had significantly shorter distant metastasis-free survival (DMFS), progression-free survival (PFS) and locoregional recurrence-free survival (LRRFS). Although not statistically significant, overall survival (OS) also tended to be worse in the high-expression group, with clear separation of survival curves. In vitro experiments demonstrated that loss of HSPA5 sensitized C666-1R cells to irradiation, whereas forced HSPA5 expression conferred relative radioresistance in C666-1 cells. Following irradiation, HSPA5 knockout markedly reduced the migration and invasion of C666-1R cells, while HSPA5 overexpression enhanced these abilities in C666-1 cells.

conclusionHSPA5 overexpression correlates with poorer prognosis in NPC and acts as a key driver of post-irradiation survival and dissemination. HSPA5 is a promising biomarker for predicting radiotherapy response and clinical outcomes, and its therapeutic inhibition may help overcome radioresistance and metastasis in NPC.