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INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer
Damiano Scopetti1, Danilo Piobbico1, Cinzia Brunacci1
1Department of Medicine and Surgery, Section of General Pathology, University of Perugia, Perugia- Italy.
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.
Insights
Insulin-like 4 (INSL4) promotes non-small-cell lung cancer (NSCLC) growth in some cells, but protein levels vary. High INSL4 mRNA in patients inversely correlates with survival, suggesting post-transcriptional regulation impacts therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer death with limited prognostic improvements.
- The role of the relaxin-family peptide, Insulin-like 4 (INSL4), in NSCLC pathogenesis is largely unexplored.
Purpose of the Study:
- To investigate the functional role of INSL4 in NSCLC cell growth and tumorigenesis.
- To explore the underlying molecular mechanisms and signaling pathways affected by INSL4 overexpression.
- To correlate INSL4 expression with patient prognosis in NSCLC.
Main Methods:
- Overexpression of INSL4 in NSCLC cell lines (H1299 and A549) to assess in vitro growth and tumorigenic potential.
- Tumor development studies in a patient-derived tumor xenograft mouse model.
- Analysis of INSL4 mRNA and protein levels across multiple NSCLC cell lines and patient cohorts.
- Correlation analysis between INSL4 expression and Overall Survival in NSCLC patients.
Main Results:
- INSL4 overexpression promoted cell growth in vitro (H1299) and tumor growth in vivo in a xenograft model.
- A contrasting lack of effect was observed in A549 cells despite high basal INSL4 mRNA, indicating cell-specific responses.
- Significant discrepancies between INSL4 mRNA and protein levels were noted in cell lines and NSCLC patients.
- A significant inverse correlation was found between INSL4 expression and Overall Survival in a NSCLC patient cohort.
Conclusions:
- INSL4 exhibits a context-dependent role in NSCLC, promoting tumor growth in specific cell types and models.
- Post-transcriptional modifications significantly influence INSL4 protein levels, complicating its assessment as a therapeutic target.
- Clinical evaluation of INSL4 in NSCLC requires consideration of both mRNA and protein expression for precision therapy.
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