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Overexpressed FAM111B degrades GSDMA to promote esophageal cancer tumorigenesis and cisplatin resistance

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Abstract

Background

Chemotherapeutic agents such as cisplatin are commonly used in patients with clinically unresectable or recurrent esophageal cancer (ESCA). However, patients often develop resistance to cisplatin, which in turn leads to a poor prognosis. Studies have shown that FAM111B may be involved in the development of tumors as an oncogene or tumor suppressor gene. However, the pathological role and corresponding mechanism of FAM111B in ESCA are still unclear.

Methods

The GEPIA web tool, ENCORI Pan-Cancer Analysis Platform and UALCAN-TCGA database were used to study the expression of FAM111B in ESCA. CCK-8, angiogenesis, Transwell and xenograft assays were applied to explore the biological function of FAM111B in ESCA. Western blot, RT-qPCR, and RNA-seq analyses were applied to study the FAM111B/GSDMA axis in the progression of ESCA cells. CCK-8 and xenograft assays were used to study the role of the FAM111B/GSDMA axis in determining the sensitivity of ESCA to cisplatin.

Results

Our results demonstrated that FAM111B is highly expressed in ESCA tissues compared to normal tissues. We showed that FAM111B promotes the progression of ESCC cells by binding to GSDMA and that the trypsin protease domain is essential for the activity of FAM111B. Furthermore, we showed that the FAM111B/GSDMA axis regulates cisplatin sensitivity in ESCA.

Conclusions

Overall, we identified a novel FAM111B/GSDMA axis regulating ESCA tumorigenesis and chemosensitivity, at least in ESCC cells.

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Data availability

The databases used and/or analyzed during the current study are available from the corresponding authors (Xiaoxiong Xiao, E-mail: xiaoxx1988@csu.edu.cn) on reasonable request.

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Acknowledgements

Not applicable.

Funding

This work were supported by grants from the National Natural Science Youth Foundation of China (Grant No. 82203838 (Xiaoxiong Xiao)); Natural Science Foundation General Program of Hunan Province (Grant No. 2022JJ40830 (Xiaoxiong Xiao)); Natural Science Foundation General Program of Changsha City (Grant No. kq2014290 (Xiaoxiong Xiao)); National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases (Lung Cancer, grant number: z027002 (Xiaoxiong Xiao)); National Natural Science Foundation of China (Grant No. 81772800, 82072945 (Pian Liu)).

Author information

Authors and Affiliations

  1. Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Haiqin Wang & Jiajing Chen

  2. Hunan Clinical Medical Research Center for Geriatric Syndrome, Changsha, Hunan, China

    Haiqin Wang & Jiajing Chen

  3. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

    Haohui Wang

  4. Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

    Haohui Wang

  5. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Cancer Center, Wuhan, Hubei, China

    Pian Liu

  6. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Pian Liu

  7. Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Xiaoxiong Xiao

  8. Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Xiaoxiong Xiao

  9. National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China

    Xiaoxiong Xiao

Authors
  1. Haiqin Wang
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  2. Haohui Wang
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Contributions

Haiqin Wang. supervised the experiments, and was responsible for bioinformatics and statistical analysis. Haohui Wang. carried out the in vitro and in vivo experiments, and wrote the original draft. Jiajing Chen. collaborated to collect specimens and record clinical information. Pian Liu. conducted the major revision work, and provided critical reviews. Xiaoxiong Xiao. generated the study design, provided the clinical specimens and revised the manuscript.

Corresponding authors

Correspondence to Pian Liu or Xiaoxiong Xiao.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at Xiangya hospital, Central South University.

Consent for publication

All subjects have written informed consent.

Conflict of interest

The authors have declared that no conflict of interest.

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Haiqin Wang and Haohui Wang contributed equally.

Supplementary Information

Below is the link to the electronic supplementary material.

13402_2023_871_MOESM1_ESM.tif

Supplementary file1 Supplementary figure 1 A and B, The univariate and multivariate Cox regression analyses through the GEO dataset GSE53622. p values as indicated. C and D, Lymph node metastasis of KYSE410 cells with FAM111B knockdown. E, The expression of SNAI1 in RNA-seq of FAM111B. Fand G, KYSE410 and TE-1 cells were infected with shControl, shFAM111B #1, or shFAM111B #2 for 72 h. Cells were collected for RT-qPCR analysis (F), and Western blot analysis (G). H, The excised subcutaneous tumors of nude mice were subjected to IHC staining of SNAI1. Data presents as mean ± SD with six replicates. ***, p < 0.001 (TIF 35268 KB)

13402_2023_871_MOESM2_ESM.tif

Supplementary file2 Supplementary figure 2 A and B, KYSE410 cells were transfected with indicated shRNAs for 72 h. Cells were collected and subcutaneously injected into the nude mice. The tumor growth curve was shown in panel B. Data presents as mean ± SD with six replicates. ***, p < 0.001. C and D, KYSE410 and TE-1 cells were transfected with indicated shRNAs for 72 h and treated with cisplatin, cells were collected for Western blot analysis to measure the expression of cleaved caspase 3. ***, p < 0.001. E and F, The excised subcutaneous tumors of nude mice were subjected to IHC staining of cleaved caspase 3. Data presents as mean ± SD with six replicates. ***, p < 0.001 (TIF 47227 KB)

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Wang, H., Wang, H., Chen, J. et al. Overexpressed FAM111B degrades GSDMA to promote esophageal cancer tumorigenesis and cisplatin resistance. Cell Oncol. 47, 343–359 (2024). https://doi.org/10.1007/s13402-023-00871-0

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