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CAF-derived midkine promotes EMT and cisplatin resistance by upregulating lncRNA ST7-AS1 in gastric cancer

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Abstract

This study aimed to investigate the role of cancer-associated fibroblast (CAF)-derived midkine (MK) in cisplatin (DDP) resistance. The primary cultures of CAFs and non-cancer fibroblasts (NFs) were isolated and purified. The DDP-resistant gastric cancer (GC) cells were cultured with CAF-conditioned medium. QRT-PCR and Elisa assays were employed to determine MK expression. The expression of ST7-AS1 was measured by qRT-PCR. The impact of CAFs, MK, and ST7-AS1 silencing on DDP resistance was determined by MTT and Annexin V/PI staining assay. Expression of EMT markers and PI3K/AKT was determined by Western blot and qRT-PCR. The role of MK in DDP resistance was confirmed in a xenograft model. Incubation with CAF-conditioned medium increased the IC50 to DDP. Also, incubation with CAF-conditioned medium increased cell viability, reduced cell apoptosis, and promoted EMT in DDP-resistant GC cells, which were all blocked with MK neutralization antibody treatment. MK increased the DDP resistance and upregulated the expression of ST7-AS1 in DDP-resistant GC cells. Additionally, ST7-AS1 knockdown increased the sensitivity to DDP by inhibiting EMT. Moreover, ST7-AS1 knockdown significantly decreased the phosphorylation of PI3K and AKT, and suppressed EMT, which were restored by MK addition. Finally, MK promoted tumor growth and DDP resistance in a mice model bearing the SGC-7901/DDP xenografts. CAF-derived MK promotes EMT-mediated DDP resistance via upregulation of ST7-AS1 and activation of PI3K/AKT pathway.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Not applicable.

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Funding

This work was supported by General Projects of Hunan Natural Science Foundation (2019JJ40493).

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Authors and Affiliations

  1. Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People’s Republic of China

    Ke-Da Yang, Ying Wang, Qing-Ling Li, Bai-Hua Luo & De-Yun Feng

  2. Department of Gynecology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, People’s Republic of China

    Fan Zhang

  3. Department of Geriatric Surgery, Xiangya Hospital, Central South University, No.87, Xiangya Road, Changsha, 410008, Hunan Province, People’s Republic of China

    Zhi-Jun Zeng

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  1. Ke-Da Yang
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Contributions

Guarantor: Z-JZ; concepts: Z-JZ, D-YF; design: D-YF; literature research: K-DY; clinical studies: YW; experimental studies: Q-LL; data acquisition: FZ; analysis: B-HL; manuscript preparation: YW; manuscript editing: Z-JZ; and manuscript review: Z-JZ.

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Correspondence to Zhi-Jun Zeng.

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All experiments were performed with the approval by the Research Ethics Committee of Xiangya Hospital of Central South University (Changsha, China).

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Yang, KD., Wang, Y., Zhang, F. et al. CAF-derived midkine promotes EMT and cisplatin resistance by upregulating lncRNA ST7-AS1 in gastric cancer. Mol Cell Biochem 477, 2493–2505 (2022). https://doi.org/10.1007/s11010-022-04436-x

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