1. Cancer Biology
  2. Immunology and Inflammation

VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer

  1. Lei Yang  Is a corresponding author
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu  Is a corresponding author
  8. Zhenjun Wang  Is a corresponding author
  1. Beijing Chao-Yang Hospital, China
  2. Beijing Chest Hospital, China
https://doi.org/10.7554/eLife.79811
Share this article
Cite this article
  1. Lei Yang
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu
  8. Zhenjun Wang
(2022)
VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
eLife 11:e79811.
https://doi.org/10.7554/eLife.79811
  2. Download BibTeX
  3. Download .RIS

Abstract

Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-β pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-β signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-β/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.

Data availability

RNA sequencing data set of HCT116 sgControl and sgVPS cells were deposited in Sequence Read Archive (PRJNA716724) and Dryad Digital Repository (10.5061/dryad.qnk98sfk6).

The following data sets were generated

Article and author information

Author details

  1. Lei Yang

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    yl6649084@mail.ccmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3718-2138

  2. Xichen Dong

    Medical Research Center, Beijing Chao-Yang Hospital, Beijign, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Zheng Liu

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Jinjing Tan

    Department of Cellular and Molecular Biology, Beijing Chest Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Xiaoxi Huang

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Tao Wen

    Medical Research Center, Beijing Chao-Yang Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Hao Qu

    Department of General Surgery, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    13701320206@163.com
    Competing interests
    The authors declare that no competing interests exist.

  8. Zhenjun Wang

    Department of General Surgery, Beijing Chao-Yang Hospital, Beijing, China
    For correspondence
    drzhenjun@163.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

Natural Science Foundation of China (81802349)

  • Lei Yang

National Science Foundation of China (8213234)

  • Tao Wen

Beijing Natural Science Foundation (7192070)

  • Lei Yang

Beijing Municipal of Hospitals Incubating Program (PX2018013)

  • Lei Yang

Scientific Research Project of Beijing Educational Committee (KM20190025016)

  • Lei Yang

Open Project of Key Laboratory of Cardiovascular Disease Medical Engineering, Ministry of Education (2019XXG-KFKT-03)

  • Lei Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experimental protocols were approved (AEEI-2021-105) according to the guidelines of the Ethics Committee for Animal Testing of Capital Medical University.

Human subjects: All sample donors provided informed consent, and the study was conducted under the approval (2018-ke-24) of the Institutional Ethics Committee from Beijing Chaoyang Hospital of Capital Medical University between 2018 and 2020 samples were collected from patients with CRC who did not receive chemotherapy or radiotherapy before surgery.

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 831
    views
  • 232
    downloads
  • 12
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Lei Yang
  2. Xichen Dong
  3. Zheng Liu
  4. Jinjing Tan
  5. Xiaoxi Huang
  6. Tao Wen
  7. Hao Qu
  8. Zhenjun Wang
(2022)
VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer
eLife 11:e79811.
https://doi.org/10.7554/eLife.79811

Share this article

https://doi.org/10.7554/eLife.79811

Categories and tags

Research organisms

Further reading

    1. Cancer Biology
    2. Cell Biology

    Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications

    Ida Marie Boisen, Nadia Krarup Knudsen ... Martin Blomberg Jensen
    Research Article

    Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.

    1. Cancer Biology

    TAK1-mediated phosphorylation of PLCE1 represses PIP2 hydrolysis to impede esophageal squamous cancer metastasis

    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology

    Breast Cancer: How cell crowding causes cancer cells to spread

    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.