Abstract 6178: Loss of DAB2IP promotes resistance to radiation in rectal cancer by activating HIF-1α

Abstract

Abstract Rectal cancer is one of the most common cancers in the United State. It shows that approximately 72.20% of the diagnosed rectal cancers are T3-4N0 or TxN+ from the SEER database. Preoperative radiotherapy has been performed as a prevalent therapy to decrease the local recurrence after total mesorectal excision. However, some patients could not get benefits from the local radiotherapy because of the resistance to radiation. While different expressions of numerous proteins have been found in radiation resistant cancer, the mechanism has been still veiled. Previously, we reported that DAB2IP, a novel member of the Ras GTPase-activating protein family, was down-regulated in various human cancers. DAB2IP functions as a scaffold protein to balance proliferation and apoptosis, and also inhibits metastasis in prostate cancer cells. In CRC, loss of DAB2IP increases the properties of cancer stem cells by regulating the NF-kB signal pathway, which also indicates the poor survival outcome. However, the role and mechanism of DAB2IP involving the resistance to radiation has not been elucidated. In this study, firstly, we compared the expression of DAB2IP in rectal cancers sensitive (42 patients) and non-sensitive (47 patients) to radiation by immunohistochemistry. Our data showed that non- or low-expression of DAB2IP was found in patients resistant to radiation (P<0.001). And these patients had worse disease free survival than high DAB2IP expression patients (p<0.01). Multivariate analyses indicated that DAB2IP expression level was an independently prognostic marker for survival of patients with rectal cancer (p<0.05). Then, we explored the biological function of DAB2IP by knocking down endogenous DAB2IP in cultured rectal cancer cell line SW837. Our results showed that knocking down DAB2IP in SW837 increased the survival rate when exposed to 2Gy dose radiation demonstrated by MTT assay and Anexin V/PI assay in flow cytometery. In xenograft model, SW837 with DAB2IP knocking down grew faster by recording the growth curve even if given total 10Gy dose radiation. Moreover, we found the amount of cleaved PARP and phosphorylated γ-H2AX decreased in DAB2IP knocking down cells exposed to 2Gy dose radiation for 6h. In addition, loss of DAB2IP could promote HIF-1α expression in nucleus and activate the signal pathway by HIF-1α luciferase analysis. In SW837 with DAB2IP knocking down, knocking down the HIF-1a by siRNA could almost rescue DAB2IP loss inducing the resistance to radiation. Taken together, our data provides strong evidence that loss of DAB2IP may contribute to the resistance to radiation in rectal cancer by activating the HIF-1α pathway. Citation Format: Shenglan Yang, Jiang Min, Liang liu, Daxing Xie. Loss of DAB2IP promotes resistance to radiation in rectal cancer by activating HIF-1α [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6178.