Prognostic impact of mRNA levels of LGR5 transcript variants in OSCC patients

Swetlana RotEmail author View ORCID ID profile,
Tom Kaune,
Helge Taubert,
Thomas Greither,
Johanna Kotrba,
Antje Güttler,
Henri Wichmann,
Udo Bilkenroth,
Andreas Wienke,
Bilal Al-Nawas,
Matthias Bache,
Dirk Vordermark,
Claudia Wickenhauser,
Daniel Bethmann†,
Alexander W. Eckert† and
Matthias Kappler†

†Contributed equally

BMC Cancer201919:155

https://doi.org/10.1186/s12885-019-5327-8

Received: 28 February 2018
Accepted: 28 January 2019
Published: 15 February 2019

Open Peer Review reports

Abstract

Background

The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5–8) has yet to be thoroughly investigated.

Methods

Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers.

Results

An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5allmRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1–3.7; HR = 3.2; p = 0.01; 95% CI: 1.3–8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2–7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).

Conclusion

The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.