# RCC1 Domain‐Containing Protein 1 Promotes Colon Cancer Malignant Progression by Activating Autophagy‐Dependent WNT5A Secretion in Cancer‐Associated Fibroblasts

**Authors:** Chao Liu, Sheng Xu, Yuanyuan Liu, Yuntian Tang

PMC · DOI: 10.1002/snz2.70013 · Journal of the Royal Society of New Zealand · 2026-01-18

## TL;DR

A protein called RCCD1 helps colon cancer grow by triggering a chain of events in nearby cells that promote cancer spread.

## Contribution

Identifies RCCD1 as a novel driver of colon cancer progression through autophagy-dependent WNT5A secretion in cancer-associated fibroblasts.

## Key findings

- RCCD1 is upregulated in colon cancer and correlates with poor prognosis.
- RCCD1 activates autophagy in cancer-associated fibroblasts, leading to WNT5A secretion.
- WNT5A promotes tumor cell invasion and epithelial-mesenchymal transition via the Wnt/CaMKII/ERK pathway.

## Abstract

Background: Autophagy plays a dual role in colon cancer, but its mechanisms in tumor‐stroma interactions are unclear.

Methods: Using TCGA‐COAD and GSE161277 datasets, we identified autophagy‐related prognostic genes via bioinformatics and machine learning. RCCD1's role was further investigated using single‐cell RNA‐seq and functional coculture assays (fibroblasts/HCT116 cells), validated in clinical samples.

Results: RCCD1 was upregulated in colon cancer and cancer‐associated fibroblasts (CAFs), correlating with poor prognosis. In CAFs, RCCD1 activated AMPK/mTOR/ULK1 signaling, enhancing autophagy and driving WNT5A secretion. This activated the Wnt/CaMKII/ERK pathway in tumor cells, promoting EMT, proliferation, and invasion. These effects were reversed by autophagy inhibition or WNT5A neutralization.

Conclusion: The RCCD1‐autophagy‐WNT5A axis is a critical mediator of protumorigenic CAF‐tumor cell crosstalk, representing a novel therapeutic target for colon cancer.

RCCD1 is upregulated in colon cancer and cancer‐associated fibroblasts (CAFs). In CAFs, RCCD1 overexpression activates AMPK/mTOR/ULK1 signaling, enhancing autophagy. This stimulates autophagic secretion of WNT5A. WNT5A then activates the nonclassical Wnt/CaMKII/ERK pathway in tumor cells, promoting epithelial‐mesenchymal transition (EMT), proliferation, invasion, and migration. Blockade of autophagy or WNT5A reverses these effects. The RCCD1‐autophagy‐WNT5A axis is a key mediator of protumorigenic CAF‐tumor crosstalk and a novel therapeutic target.© 2026 WILEY‐VCH GmbH

## Linked entities

- **Genes:** RCCD1 (RCC1 domain containing 1) [NCBI Gene 91433], PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562], MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475], ULK1 (unc-51 like autophagy activating kinase 1) [NCBI Gene 8408], WNT5A (Wnt family member 5A) [NCBI Gene 7474], CAMK2G (calcium/calmodulin dependent protein kinase II gamma) [NCBI Gene 818], EPHB2 (EPH receptor B2) [NCBI Gene 2048]
- **Proteins:** PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1), MTOR (mechanistic target of rapamycin kinase), ULK1 (unc-51 like autophagy activating kinase 1), WNT5A (Wnt family member 5A), CAMK2G (calcium/calmodulin dependent protein kinase II gamma), EPHB2 (EPH receptor B2)
- **Diseases:** colon cancer (MONDO:0002032)

## Full-text entities

- **Genes:** CAMK2G (calcium/calmodulin dependent protein kinase II gamma) [NCBI Gene 818] {aka CAMK, CAMK-II, CAMKG, MRD59}, ULK1 (unc-51 like autophagy activating kinase 1) [NCBI Gene 8408] {aka ATG1, ATG1A, UNC51, Unc51.1, hATG1}, PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1) [NCBI Gene 5562] {aka AMPK, AMPK alpha 1, AMPKa1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, RCCD1 (RCC1 domain containing 1) [NCBI Gene 91433], WNT5A (Wnt family member 5A) [NCBI Gene 7474] {aka hWNT5A}
- **Diseases:** Cancer (MESH:D009369), Colon Cancer (MESH:D015179)

## Full text

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## Figures

9 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12959610/full.md

## References

41 references — full list in the complete paper: https://tomesphere.com/paper/PMC12959610/full.md

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Source: https://tomesphere.com/paper/PMC12959610