PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Jie Tao; Lin Yin; Ao Wu; Jiaoli Zhang; Jingpu Zhang; Huichun Shi; Siyuan Liu; Liangfei Niu; Li Xu; Yanling Feng; Shixian Lian; Lei Li; Liyan Zeng; Xianmin Meng; Xiaohui Zhou; Tiefu Liu; Lijun Zhang

doi:10.3389/fonc.2022.836087

PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Front Oncol. 2022 Jul 4:12:836087. doi: 10.3389/fonc.2022.836087. eCollection 2022.

Authors

Jie Tao¹, Lin Yin¹, Ao Wu¹, Jiaoli Zhang¹, Jingpu Zhang¹, Huichun Shi¹, Siyuan Liu², Liangfei Niu¹, Li Xu¹, Yanling Feng³, Shixian Lian⁴, Lei Li⁴, Liyan Zeng⁵, Xianmin Meng⁵, Xiaohui Zhou⁶, Tiefu Liu¹, Lijun Zhang^{1

5}

Affiliations

¹ Scientific Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
² The College of Information, Mechanical and Electrical Engineering, Shanghai Normal University, Shanghai, China.
³ Clinical Pathology Laboratory, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁴ Department of Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁵ Department of Clinical Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
⁶ Animal Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Abstract

Background: Chronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation.

Methods: The animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues.

Results: AOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm², which was significantly decreased to 5.85 ± 0.95 mm² by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer.

Conclusions: Persistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.

Keywords: PDIA2; chronic colitis; colon cancer; endoplasmic reticulum stress; malignant transformation; metabolic reprogramming.