HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer

Yi-Jung Huang; Yi-Ting Chen; Chun-Ming Huang; Shih-Hsun Kuo; Yan-You Liao; Wun-Ya Jhang; Shuo-Hung Wang; Chien-Chih Ke; Yu-Hsiang Huang; Chiu-Min Cheng; Ming-Yii Huang; Chih-Hung Chuang

doi:10.3390/cancers14164053

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer

Cancers (Basel). 2022 Aug 22;14(16):4053. doi: 10.3390/cancers14164053.

Authors

Yi-Jung Huang^{1

2}, Yi-Ting Chen^{3

4}, Chun-Ming Huang^{5

6

7

8}, Shih-Hsun Kuo⁵, Yan-You Liao⁹, Wun-Ya Jhang¹⁰, Shuo-Hung Wang¹⁰, Chien-Chih Ke^{2

11

12}, Yu-Hsiang Huang¹³, Chiu-Min Cheng¹⁴, Ming-Yii Huang^{1

5

6

7}, Chih-Hung Chuang^{1

2

10}

Affiliations

¹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
² Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁴ Department of Pathology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁶ Department of Radiation Oncology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁷ Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁸ Department of Radiation Oncology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁹ School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹⁰ Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹¹ Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹² Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
¹³ Post-graduate Year Training (PGY), Department of Clinical Education and Training, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
¹⁴ Department and Graduate Institute of Aquaculture, National Kaohsiung University of Science and Techology, Kaohsiung 80708, Taiwan.

Abstract

Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.

Keywords: CCRT; HIF-1α; HIF-1α inhibitors; HbA1c; O-GlcNAc transferase (OGT); concurrent chemoradiotherapy (CCRT); glucose transport 1 (GLUT1); glycosylated hemoglobin; hyperglycemia; hypoxia-inducible factor-1 alpha (HIF-1α); rectal cancer.

Abstract

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