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Background <p>TCOF1 is a nucleolar protein involved in ribosome biogenesis, DNA damage response, and mitotic regulation. Germline <i>TCOF1</i> mutations are associated with Treacher-Collins syndrome, a rare congenital disorder characterized by craniofacial abnormalities. Clear cell renal cell carcinoma (ccRCC), the most prevalent form of kidney cancer, exhibits pronounced nuclear and nucleolar pleomorphism, which correlates with tumour aggressiveness. The ccRCC grading system relies on microscopic evaluation of nuclear and nucleolar features. Here, we hypothesized that TCOF1 contributes to ccRCC tumorigenesis.</p> Methods <p>The study involved 200 tissue samples from ccRCC patients, two ccRCC-derived cell lines, and the publicly available cancer datasets. The used techniques included siRNA transfections, proliferation, viability, migration, and adhesion assays, proteomic and transcriptomic analyses, Western blot, real-time PCR, and angiogenesis evaluation using HUVEC cells.</p> Results <p>TCOF1 expression was elevated in ccRCC tumours and correlated with higher nucleolar grade and poorer patient survival. TCOF1 depletion altered the expression of multiple genes and proteins involved in the Golgi secretory pathway, including AVL9, GOLGA4, GOPC, RPS6KA5, SCAMP1, SEC24B, and STEAP3. These changes led to enhanced secretion of the anti-angiogenic thrombospondin 1 and suppression of angiogenesis. Furthermore, TCOF1 silencing downregulated several proteins implicated in craniofacial development, such as DCAF7 (aka WDR68), CHUK, APAF1, DICER1, and ETS1.</p> Conclusions <p>To our knowledge, this is the first study linking a nucleolar TCOF1 protein to the regulation of cellular secretion. Our findings suggest that elevated TCOF1 expression may disrupt the Golgi secretory pathway, inhibit thrombospondin 1 secretion, and promote angiogenesis in ccRCC. Our study also contributes to the understanding of the molecular consequences of TCOF1 dysfunction in Treacher-Collins syndrome.</p>

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TCOF1 affects Golgi secretory pathway contributing to the angiogenesis in renal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Małgorzata Grzanka,
  • Piotr Popławski,
  • Jacek R. Wiśniewski,
  • Roksana Iwanicka-Nowicka,
  • Helena Kossowska,
  • Marta Koblowska,
  • Beata Rybicka,
  • Alex Białas,
  • Agnieszka Piekiełko-Witkowska

摘要

Background

TCOF1 is a nucleolar protein involved in ribosome biogenesis, DNA damage response, and mitotic regulation. Germline TCOF1 mutations are associated with Treacher-Collins syndrome, a rare congenital disorder characterized by craniofacial abnormalities. Clear cell renal cell carcinoma (ccRCC), the most prevalent form of kidney cancer, exhibits pronounced nuclear and nucleolar pleomorphism, which correlates with tumour aggressiveness. The ccRCC grading system relies on microscopic evaluation of nuclear and nucleolar features. Here, we hypothesized that TCOF1 contributes to ccRCC tumorigenesis.

Methods

The study involved 200 tissue samples from ccRCC patients, two ccRCC-derived cell lines, and the publicly available cancer datasets. The used techniques included siRNA transfections, proliferation, viability, migration, and adhesion assays, proteomic and transcriptomic analyses, Western blot, real-time PCR, and angiogenesis evaluation using HUVEC cells.

Results

TCOF1 expression was elevated in ccRCC tumours and correlated with higher nucleolar grade and poorer patient survival. TCOF1 depletion altered the expression of multiple genes and proteins involved in the Golgi secretory pathway, including AVL9, GOLGA4, GOPC, RPS6KA5, SCAMP1, SEC24B, and STEAP3. These changes led to enhanced secretion of the anti-angiogenic thrombospondin 1 and suppression of angiogenesis. Furthermore, TCOF1 silencing downregulated several proteins implicated in craniofacial development, such as DCAF7 (aka WDR68), CHUK, APAF1, DICER1, and ETS1.

Conclusions

To our knowledge, this is the first study linking a nucleolar TCOF1 protein to the regulation of cellular secretion. Our findings suggest that elevated TCOF1 expression may disrupt the Golgi secretory pathway, inhibit thrombospondin 1 secretion, and promote angiogenesis in ccRCC. Our study also contributes to the understanding of the molecular consequences of TCOF1 dysfunction in Treacher-Collins syndrome.