Long-term DEHP/MEHP exposure promotes colorectal cancer stemness associated with glycosylation alterations

Pei-Chun Shih; Hsin-Pao Chen; Ching-Cheng Hsu; Chung-Hsien Lin; Chou-Yuan Ko; Chao-Wen Hsueh; Cheng-Yi Huang; Tian-Huei Chu; Cheng-Chun Wu; Yu-Cheng Ho; Ngoc Uyen Nhi Nguyen; Shih-Chung Huang; Cheng-Chieh Fang; Shiow-Jyu Tzou; Yueh-Jung Wu; Tung-Yuan Chen; Chuan-Fa Chang; Yung-Kuo Lee

doi:10.1016/j.envpol.2023.121476

Long-term DEHP/MEHP exposure promotes colorectal cancer stemness associated with glycosylation alterations

Environ Pollut. 2023 Jun 15:327:121476. doi: 10.1016/j.envpol.2023.121476. Epub 2023 Mar 28.

Authors

Pei-Chun Shih¹, Hsin-Pao Chen², Ching-Cheng Hsu³, Chung-Hsien Lin¹, Chou-Yuan Ko⁴, Chao-Wen Hsueh⁴, Cheng-Yi Huang⁵, Tian-Huei Chu⁶, Cheng-Chun Wu⁷, Yu-Cheng Ho⁷, Ngoc Uyen Nhi Nguyen⁸, Shih-Chung Huang⁹, Cheng-Chieh Fang¹⁰, Shiow-Jyu Tzou¹¹, Yueh-Jung Wu¹², Tung-Yuan Chen¹², Chuan-Fa Chang¹, Yung-Kuo Lee¹³

Affiliations

¹ Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
² Division of Colon and Rectal Surgery, Department of Surgery, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.
³ Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas TX 75390, USA.
⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan; Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
⁵ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
⁶ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
⁷ School of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan.
⁸ Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas TX 75390, USA.
⁹ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Division of Cardiology, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan; Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
¹⁰ Primo Biotechnology Co., Ltd, Taipei, 104511, Taiwan.
¹¹ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Department of Nursing, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan; Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
¹² Division of Colorectal Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
¹³ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan. Electronic address: yungkuolee@gmail.com.

PMID: 36997141
DOI: 10.1016/j.envpol.2023.121476

Abstract

Plasticizers are considered as environmental pollution released from medical devices and increased potential oncogenic risks in clinical therapy. Our previous studies have shown that long-term exposure to di-ethylhexyl phthalate (DEHP)/mono-ethylhexyl phthalate (MEHP) promotes chemotherapeutic drug resistance in colorectal cancer. In this study, we investigated the alteration of glycosylation in colorectal cancer following long-term plasticizers exposure. First, we determined the profiles of cell surface N-glycomes by using mass spectrometry and found out the alterations of α2,8-linkages glycans. Next, we analyzed the correlation between serum DEHP/MEHP levels and ST8SIA6 expression from matched tissues in total 110 colorectal cancer patients. Moreover, clinical specimens and TCGA database were used to analyze the expression of ST8SIA6 in advanced stage of cancer. Finally, we showed that ST8SIA6 regulated stemness in vitro and in vivo. Our results revealed long-term DEHP/MEHP exposure significantly caused cancer patients with poorer survival outcome and attenuated the expression of ST8SIA6 in cancer cells and tissue samples. As expected, silencing of ST8SIA6 promoted cancer stemness and tumorigenicity by upregulating stemness-associated proteins. In addition, the cell viability assay showed enhanced drug resistance in ST8SIA6 silencing cells treated with irinotecan. Besides, ST8SIA6 was downregulated in the advanced stage and positively correlated with tumor recurrence in colorectal cancer. Our results imply that ST8SIA6 potentially plays an important role in oncogenic effects with long-term phthalates exposure.

Keywords: Colorectal cancer; Environmental pollution; Glycosylation alterations; Long-term phthalates exposure; Oncogenic risks; ST8SIA6.

MeSH terms

Colorectal Neoplasms*
Diethylhexyl Phthalate* / analysis
Glycosylation
Humans
Plasticizers / analysis
Sialyltransferases / metabolism

Substances

Plasticizers
mono-(2-ethylhexyl)phthalate
Diethylhexyl Phthalate
phthalic acid
ST8SIA6 protein, human
Sialyltransferases