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Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway

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Abstract

Purpose

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis.

Methods

The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH4CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo.

Results

We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way.

Conclusions

Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.

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Data Availability

All supporting data generated or analyzed during this study are available.

Abbreviations

DDR1:

Discoidin Domain Receptor 1

SLC1A5:

Solute Carrier Family 1 Member 5

mTORC1:

Mechanistic Target of Rapamycin Kinase Complex 1

4EBP1:

Eukaryotic Translation Initiation Factor 4E Binding Protein 1

RPS6K:

Ribosomal Protein S6 Kinase

CCK8:

Cell Counting Kit-8

CHX:

Cycloheximide

OS:

Overall survival

HCC:

Hepatocellular carcinoma

IHC:

Immunohistochemistry

OD:

Optical density

PCR:

Polymerase Chain Reaction

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Acknowledgements

Our work was supported by the National Natural Science Foundation of China (No. 81572427, 81874189, 81572855, 81874065, and 81874149), the National Basic Research Program of China (2020YFA0710700), the State Key Project on Infection Disease of China (No. 2018ZX10723204–003) and Tongji Hospital (HUST) Foundation for Excellent Young Scientist (No. 2020YQ05).

Funding

This work was supported by the National Natural Science Foundation of China (No. 81572427, 81874189, 81572855, 81874065, and 81874149), the National Basic Research Program of China (2020YFA0710700), the State Key Project on Infection Disease of China (No. 2018ZX10723204–003) and Tongji Hospital (HUST) Foundation for Excellent Young Scientist (No. 2020YQ05).

Author information

Author notes

  1. Yonglong Pan, Mengzhen Han and Xiaochao Zhang contributed equally to this work.

Authors and Affiliations

  1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China

    Yonglong Pan, Mengzhen Han, Xiaochao Zhang, Yi He, Chaoyi Yuan, Yixiao Xiong, Xinxin Li, Chenglong Zeng, Kan Lu, He Zhu, Xun Lu, Qiumeng Liu, Huifang Liang, Zhibin Liao, Zeyang Ding, Zhanguo Zhang, Xiaoping Chen, Wanguang Zhang & Bixiang Zhang

  2. Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China

    Yonglong Pan, Mengzhen Han, Xiaochao Zhang, Yi He, Chaoyi Yuan, Yixiao Xiong, Xinxin Li, Chenglong Zeng, Kan Lu, He Zhu, Xun Lu, Qiumeng Liu, Huifang Liang, Zhibin Liao, Zeyang Ding, Zhanguo Zhang, Xiaoping Chen, Wanguang Zhang & Bixiang Zhang

  3. Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China

    Zhibin Liao, Zeyang Ding, Zhanguo Zhang, Xiaoping Chen, Wanguang Zhang & Bixiang Zhang

  4. Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China

    Zhibin Liao, Zeyang Ding, Zhanguo Zhang, Xiaoping Chen, Wanguang Zhang & Bixiang Zhang

  5. Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China

    Zhibin Liao, Zeyang Ding, Zhanguo Zhang, Xiaoping Chen, Wanguang Zhang & Bixiang Zhang

Authors
  1. Yonglong Pan
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  2. Mengzhen Han
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  4. Yi He
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Contributions

Conception/Design: Bixiang Zhang and Wanguang Zhang; Provision of study material or patients: Yonglong Pan, Mengzhen Han and Xiaochao Zhang; Collection and/or assembly of data: Yi He, Chaoyi Yuan, Yixiao Xiong, Chenglong Zeng and Kan Lu; Data analysis and interpretation: Yonglong Pan, Mengzhen Han and Xiaochao Zhang;Manuscript writing: Yonglong Pan; Technical or material support: He Zhu, Xun Lu, Qiumeng Liu and Huifang Liang; Guiding opinions: Zhibin Liao, Zeyang Ding, Zhanguo Zhang and Xiaoping Chen; Final approval of manuscript: All authors.

Corresponding authors

Correspondence to Wanguang Zhang or Bixiang Zhang.

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Supplementary Information

Below is the link to the electronic supplementary material.

13402_2022_659_MOESM1_ESM.pdf

Supplementary file1 (PDF 979 kb) Fig1S: DDR1 promotes the proliferation, and tumorigenesis in HCC cells. a DDR1 expression level in hepatic and HCC cell lines was analyzed by Western blotting. b, c The expression level of DDR1 was detected by western blotting and qRT-PCR in DDR1 overexpression HCC cells. d, e The expression level of DDR1 was detected by western blotting and qRT-PCR in DDR1 knockdown HCC cells. f, g The effect of DDR1 overexpressing on HepG2 cell proliferation was assessed by the CCK8 assay(n=6) and colony-formation assay(n=3). h, i The effect of DDR1 knockdown on HLE cell proliferation was assessed by the CCK8 assay(n=6) and colony-formation assay(n=3). j The tumors formed by Sk-hep1-DDR1 and Sk-hep1-Vector cells were subjected to immunohistochemical staining for the proliferation marker Ki67. k The tumors formed by HLF-DDR1 shRNA and HLF-shNC shRNA cells were subjected to immunohistochemical staining for the proliferation marker Ki67.

13402_2022_659_MOESM2_ESM.pdf

Supplementary file2 (PDF 303 kb) Fig2S: DDR1 binds to SLC1A5 a Detection of SLC1A5 by mass spectrometry. b Selective genes from mass spectrometry analysis were co-immunoprecipitated with Myc-tagged DDR1.c 293T cells were transiently co-transfected with FLAG-tagged DDR1 and HA-tagged DDR1-K618A/R105A.

13402_2022_659_MOESM3_ESM.pdf

Supplementary file3 (PDF 567 kb) Fig3S: DDR1 stabilizes SLC1A5 protein expression through a kinase-independent mechanism. a, b The expression of SLC1A5 was detected by western blotting in indicated cells. c Immunoprecipitation of DDR1 from SK-hep1-vector and SK-hep1-DDR1 cell lysates pre-incubated with (+) or without (-) collagen I for 3 hours. The blots were probed with anti-phosphotyrosine antibody and anti-DDR1 antibody. Immunoprecipitation of DDR1 from HLF-scramble, HLF- shDDR1-1 and HLF-shDDR1-2 cell lysates pre-incubated with (+) or without (-) collagen I for 3 hours. The blots were probed with anti-phosphotyrosine antibody and anti-DDR1 antibody. d The expression of SLC1A5 was detected by western blotting in indicated cells with or without Collagen I stimulation(10ug/ml,3 hours).e HLE cells were pretreated with or without Collagen I (10ug/ml,3 hours) alone or in combination with ponatinib(100nM) and imatinib(100nM). The expression of SLC1A5 was detected by western blotting. f, g The expression of SLC1A5 was detected by western blotting in indicated cells with or without MG132(20mmol/L,6h). h The expression of p-mTORC1, mTORC1, p-S6K, S6K, p-4EBP1 and 4EBP1 were detected by western blotting in indicated cells.

13402_2022_659_MOESM4_ESM.pdf

Supplementary file4 (PDF 347 kb) Fig4S: SLC1A5 promotes cellular proliferation, and mTORC1 signaling pathway in HCC cells a SLC1A5 expression level in hepatic and HCC cell lines was analyzed by Western blotting. The expression level of SLC1A5 was detected by western blotting in SLC1A5 overexpression and knockdown HCC cells. b, c The protein level of SLC1A5 was examined in 62 pairs of HCC tumor tissues (T) and corresponding peritumor tissues (N) by western blot using anti-SLC1A5 antibody, where GAPDH was used as a loading control. Representative WB images were presented.

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Pan, Y., Han, M., Zhang, X. et al. Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway. Cell Oncol. 45, 163–178 (2022). https://doi.org/10.1007/s13402-022-00659-8

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