Cancer-associated fibroblasts enhance cell proliferation and metastasis of colorectal cancer SW480 cells by provoking long noncoding RNA UCA1

Abstract

Cancer-associated fibroblasts (CAFs) have been considered as major players in tumor growth and malignancy. In colorectal cancer (CRC), CAFs are attendance in high affluence and little is known about how they impact tumor progression. An increasing number of studies indicated that dysregulation of human urothelial carcinoma associated 1 (UCA1) is associated with progression of tumor and metastasis in various cancers including CRC. Nonetheless, the possible mechanisms of UCA1 actuation in CRC remain poorly understood. To address this, we elucidated the effects of conditioned medium from SW480 CRC cells/Normal fibroblast co-culture (CAF-CM) on UCA1 expression, and the cell proliferation, EMT, invasion and migration of the treated CRC cell were evaluated in vitro. Our study indicated that CAFs dramatically stimulated cell proliferation and migration of CRC cell. Furthermore, CAFs induced the EMT phenotype in CRC cell, with an associated change in the expression of EMT markers including vimentin, E-cadherin, N-cadherin and metastasis-related genes (MMPs). Moreover, we found an increased percentage of CRC cell in the S and G2/M phase induced by CAFs. Our results revealed that CAFs could induce upregulation of UCA1, leading to upregulation of mTOR. Up-regulation of UCA1/mTOR axis suppressed p27 and miR-143 while the expression of Cyclin-D1 and KRAS were significantly increased compared with control. Furthermore, UCA1 silencing in treated CRC cell suggested that upregulation of UCA1, which was induced by CAFs, regulates the expression of downstream key effectors. Taken together, these results highlight the vital role of cooperation between lncRNA UCA1 and mTOR in proliferation and metastasis which support the hypothesis that CAFs may be a prominent therapeutic target of stroma-based therapy in CRC treatment.

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Abbreviations

CAF:

Cancer-associated fibroblasts

CAF-CM:

Cancer-associated fibroblasts conditioned medium

CRC:

Colorectal cancer cell

DMSO:

Dimethyl sulfoxide

EMT:

Epithelial-to-mesenchymal transition

LncRNA:

Long noncoding RNA

MMP:

Matrix metalloproteinases

NF-CM:

Normal fibroblasts conditioned medium

qRT-PCR:

Quantitative reverse transcription–polymerase chain reaction

UCA1:

Urothelial carcinoma associated 1

siRNA:

Small interfering RNA

TFs:

Transcription factors

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Acknowledgements

This work was supported by the research deputy of University of Tabriz.

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Correspondence to Mohammad Khalaj-kondori.

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Jahangiri, B., Khalaj-kondori, M., Asadollahi, E. et al. Cancer-associated fibroblasts enhance cell proliferation and metastasis of colorectal cancer SW480 cells by provoking long noncoding RNA UCA1. J. Cell Commun. Signal. 13, 53–64 (2019). https://doi.org/10.1007/s12079-018-0471-5

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Keywords

  • Cancer-associated fibroblasts (CAFs)
  • lncRNA UCA1
  • mTOR
  • KRAS
  • miR-143
  • Colorectal cancer