Deficiency of the UBE2C/F264 Axis Underlies Intrinsic Radioresistance in Cervical Carcinoma

Intrinsic radiotherapy resistance remains a persistent
challenge
to the treatment of cervical cancer (CC), as the underlying mechanisms
remain largely elusive. In this study, proteomic profiling was combined
with in vitro and in vivo experiments
to clarify the potential mechanisms driving radiotherapy resistance.
Initially, Orbitrap Astral-based proteomic profiling of clinical specimens
revealed markedly decreased UBE2C expression in radioresistant tumors.
Subsequent functional validation with cellular and animal models of
UBE2C deficiency revealed that UBE2C is critical for preserving radiosensitivity
and its knockdown directly induced the radioresistance of CC. Furthermore,
proteomic analysis of UBE2C-knockdown CC cell lines, combined with
multilayer intersection analysis of the clinical proteomic data, revealed
that the glycolysis-associated protein F264 is potentially regulated
by UBE2C. Mechanistically, F264 regulates tumor cell dormancy to evade
radiation-induced damage. Finally, immunohistochemical analysis of
an independent clinical cohort confirmed aberrant F264 protein expression
patterns. Therefore, we hypothesize that altered UBE2C protein levels
during cervical carcinogenesis modulate F264 expression, which partially
activates tumor dormancy mechanisms, ultimately contributing to the
intrinsic radiotherapy resistance observed in a subset of CC patients
during initial treatment.