Paclitaxel is a key chemotherapeutic agent for esophageal squamous cell carcinoma (ESCC), but resistance limits its clinical benefit.We investigated whether β-IVa tubulin (TUBB4A) is associated with response to paclitaxel-based therapy and whether it affects paclitaxel-associated cellular responses in ESCC.Ninety-two patients with locally advanced or advanced ESCC who received paclitaxel-based therapy were classified as therapy-sensitive or -insensitive according to tumor regression grade or RECIST after two treatment cycles, and post-treatment tumor specimens were analyzed by immunohistochemistry.In parallel, ESCC cells were A c c e p t e d M a n u s c r i p tsubjected to TUBB4A knockdown or overexpression, UBFD1 knockdown or overexpression, CCK-8, Transwell, western blot, TUNEL, and RNA-sequencing analyses.TUBB4A protein expression was higher in post-treatment tumors from the therapy-insensitive group than in those from the therapy-sensitive group.In ECA-109 and KYSE-30 cells, TUBB4A knockdown suppressed proliferation, migration, and invasion, enhanced paclitaxel-associated apoptosis, and reduced proliferation-and cell cycle-related proteins.These findings were reproduced with an independent TUBB4A siRNA.RNA sequencing identified UBFD1 as a candidate downstream mediator.Under paclitaxel exposure, UBFD1 overexpression partially rescued the reduced viability and pro-apoptotic phenotype induced by TUBB4A knockdown, whereas UBFD1 knockdown reduced viability and enhanced paclitaxel-associated antiproliferative and pro-apoptotic effects.Conversely, TUBB4A overexpression attenuated the antiproliferative effect of paclitaxel at a fixed concentration.These findings suggest that TUBB4A is associated with poorer response to paclitaxel-based therapy and may contribute to reduced paclitaxel responsiveness in ESCC, at least in part through UBFD1.Because the clinical analysis was based on post-treatment specimens, pretreatment validation is required.
Ren et al. (Thu,) studied this question.