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J Cancer 2021; 12(13):3781-3795. doi:10.7150/jca.51332 This issue Cite

Research Paper

INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer

Damiano Scopetti1*, Danilo Piobbico1*, Cinzia Brunacci1*, Stefania Pieroni1, Guido Bellezza2, Marilena Castelli1, Vienna Ludovini3, Francesca Romana Tofanetti3, Lucio Cagini4, Angelo Sidoni2, Efisio Puxeddu5, Maria Agnese Della-Fazia1✉, Giuseppe Servillo1✉

1. Department of Medicine and Surgery, Section of General Pathology, University of Perugia, Perugia- Italy.
2. Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, University of Perugia, Perugia- Italy.
3. Medical Oncology, S. Maria Della Misericordia Hospital, Perugia, Italy.
4. Department of Medicine and Surgery, Section of internal medicine, angiology and atherosclerosis diseases.
5. Department of Medicine and Surgery, Section of internal medicine and endocrine and metabolic sciences.
*These authors contributed equally to this work.

✉ Corresponding authors: Maria Agnese Della-Fazia & Giuseppe Servillo share senior authorship. Maria Agnese Della-Fazia, Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi, 1, Perugia- Italy, tel. 075 5858111, E-mail: ma More

Citation:
Scopetti D, Piobbico D, Brunacci C, Pieroni S, Bellezza G, Castelli M, Ludovini V, Tofanetti FR, Cagini L, Sidoni A, Puxeddu E, Della-Fazia MA, Servillo G. INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer. J Cancer 2021; 12(13):3781-3795. doi:10.7150/jca.51332. https://www.jcancer.org/v12p3781.htm
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Abstract

Graphic abstract

Non-small-cell-lung cancer accounts for 80-85% of all forms of lung cancer as leading cause of cancer-related death in human. Despite remarkable advances in the diagnosis and therapy of lung cancer, no significant improvements have thus far been achieved in terms of patients' prognosis. Here, we investigated the role of INSL4 - a member of the relaxin-family - in NSCLC. We overexpressed INSL4 in NSCLC cells to analyse in vitro the growth rate and the tumourigenic features. We investigated the signalling pathways engaged in INSL4 overexpressing cells and the tumour growth ability by studying the tumour development in a patient derived tumour xenograft mouse model. We found an INSL4 cell growth promoting effect in vitro in H1299 cells and in vivo in NOD/SCID mice. Surprisingly, in NSCLC-A549 cells, INSL4 overexpression has not similar effect, despite huge basal INSL4-mRNA expression respect to H1299. The INSL4-mRNA analysis of eight different NSCLC-derived cell lines, revealed highly difference in the INSL4-mRNA amount. Transfection of NSCLC lines with INSL4-Myc showed huge level of INSL4-mRNA with a very low amount of protein expressed. Notably, similar discrepancy has been observed in NSCLC patients. However, in a cohort of NSCLC patients analysing a database, we found a significant inverse correlation between INSL4 expression and Overall Survival. By combining the in vitro and in vivo results, suggest that in patients whose NSCLC adenocarcinoma spontaneously expressed high levels of INSL4 post-transcriptional modifications affecting INSL4 do not allow to assess precision therapy in selected patients without consider protein INSL4 amount.

Keywords: INSL4, NSCLC adenocarcinoma, invasiveness, proliferation, xenograft mouse

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APA
Scopetti, D., Piobbico, D., Brunacci, C., Pieroni, S., Bellezza, G., Castelli, M., Ludovini, V., Tofanetti, F.R., Cagini, L., Sidoni, A., Puxeddu, E., Della-Fazia, M.A., Servillo, G. (2021). INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer. Journal of Cancer, 12(13), 3781-3795. https://doi.org/10.7150/jca.51332.

ACS
Scopetti, D.; Piobbico, D.; Brunacci, C.; Pieroni, S.; Bellezza, G.; Castelli, M.; Ludovini, V.; Tofanetti, F.R.; Cagini, L.; Sidoni, A.; Puxeddu, E.; Della-Fazia, M.A.; Servillo, G. INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer. J. Cancer 2021, 12 (13), 3781-3795. DOI: 10.7150/jca.51332.

NLM
Scopetti D, Piobbico D, Brunacci C, Pieroni S, Bellezza G, Castelli M, Ludovini V, Tofanetti FR, Cagini L, Sidoni A, Puxeddu E, Della-Fazia MA, Servillo G. INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer. J Cancer 2021; 12(13):3781-3795. doi:10.7150/jca.51332. https://www.jcancer.org/v12p3781.htm

CSE
Scopetti D, Piobbico D, Brunacci C, Pieroni S, Bellezza G, Castelli M, Ludovini V, Tofanetti FR, Cagini L, Sidoni A, Puxeddu E, Della-Fazia MA, Servillo G. 2021. INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer. J Cancer. 12(13):3781-3795.

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