Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling

Zhen-xiong Zhao1,2, Yan-qiu Zhang2,3, Hui Sun2,4,5, Zi-qi Chen6, Jin-jia Chang2,3, Xin Wang2,4,5, Xu Wang2,4,5, Cong Tan2,4,5, Shu-juan Ni2,4,5, Wei-wei Weng2,4,5, Meng Zhang2,4,5, Lei Wang2,4,5, Dan Huang2,4,5, Yun Feng7, Wei-qi Sheng2,4,5, Mi-die Xu2,4,5
1 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3 Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
4 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
5 Institute of Pathology, Fudan University, Shanghai 200032, China
6 Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200080, China
7 Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
Correspondence to: Yun Feng:, Wei-qi Sheng:, Mi-die Xu:,
DOI: 10.1038/s41401-022-00927-1
Received: 25 May 2022
Accepted: 25 May 2022
Advance online: 8 June 2022


Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/ Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.
Keywords: gastric cancer; cancer-associated fibroblasts; Vitamin D receptor; calcipotriol; PI3K/AKT pathway; IL-8; oxaliplatin; chemoresistance; tumor microenvironment

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