HIPK2 is a potential predictive marker of a favorable response for adjuvant chemotherapy in stage II colorectal cancer.

Abstract

Colorectal cancer (CRC) is the third most frequently diagnosed type of cancer worldwide. StageII CRC accounts for ~25% all CRC cases and their management after surgical resection remains a clinical dilemma due to the lack of reliable criteria for identifying patients who may benefit from adjuvant chemotherapy. Homeodomain‑interacting protein kinase2(HIPK2), a multifunctional kinase involved in numerous signaling pathways, serves several key roles in cell response to different types of stresses, including chemotherapy‑induced genotoxic damage. In the present study, immunohistochemistry was performed for HIPK2 on a tissue microarray of primary human tumor samples from 84patients with stageII CRC, treated (30patients) or not treated (54patients) with adjuvant chemotherapy, and sequenced for the TP53 gene, a key HIPK2 target in genotoxic damage response. It was observed that, regardless of the TP53 gene status, a high percentage of HIPK2+ cells was associated with therapeutic vulnerability in stageII CRC, suggesting a contribution of HIPK2 to drug‑response invivo. For the invitro characterization, HIPK2 was depleted in human CRC cells by CRISPR/Cas9 or RNA interference. HIPK2‑proficient and HIPK2‑defective cells were evaluated for their response to 5‑fluorouracil(5‑FU) and oxaliplatin(OXA). The results revealed that HIPK2 depletion induced resistance to 5‑FU and OXA, and that this resistance was not overcome by brusatol, an inhibitor of the antioxidant response regulator nuclear factor erythroid2‑related factor2(NRF2), which is frequently overexpressed in CRC. By contrast, cell sensitivity to 5‑FU and OXA was further induced by brusatol supplementation in HIPK2‑proficient cells, further supporting the contribution of HIPK2 in chemotherapy response. Overall, the present results suggested that HIPK2 may be a potential predictive marker for adjuvant‑treated stageII CRC and for prospective therapy with NRF2 modulators.