HOXB8 contributed to oxaliplatin chemo-resistance in colon cancer cells by activating STAT3

Abstract

Background: Homeobox B8 (HOXB8), a member of HOX family, plays a key role in the development of colorectal cancer (CRC). However, the function of HOXB8 in oxaliplatin (OXA) resistance in CRC is still unclear. This study investigated the role and precise molecular mechanism of HOXB8 in OXA-resistant CRC cells. Methods: The cell viability was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the colony forming ability was determined by colony formation assay. The silencing RNA (siRNA) approach was used to knockdown HOXB8 in CRC cells while the lentiviral transfection system was used to establish stable HOXB8 overexpressing CRC cells. The protein and mRNA levels were evaluated by western blot and real-time reverse transcription-polymerase chain reaction. Results: HOXB8 expression was upregulated in OXA-resistant HCT116 cells (HCT116/OXA) compared to its level in the parent HCT116 cells. Knockdown of HOXB8 significantly inhibited CRC cell growth by suppressing the signal transducer and activator of transcription 3 (STAT3) pathway. HOXB8 knockdown also potentiated cytotoxicity of OXA in CRC cells. Inversely, HOXB8 overexpression attenuated OXA-induced growth inhibition of HCT116 cells and RKO cells by activating STAT3 signaling. HOXB8 knockdown effectively inhibited HCT116/OXA cell viability regardless of OXA treatment by suppressing STAT3 signaling. Conclusions: These results shed light on the important functions of HOXB8 in OXA-resistant CRC and suggested that targeting HOXB8 might be an effective therapeutic strategy for select OXA-resistant CRC patients.