IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas.

INTRODUCTION: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. MATERIALS AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. CONCLUSIONS: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

Expression of IMP3 in a retrospective cohort of melanomas with selective lymph node biopsy.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3), which is a member of the insulin-like growth factor mRNA-binding protein family, is expressed at high levels in many types of cancer, where it plays an important role in cell proliferation, as well as in the processes of invasion, migration, and metastasis. Its expression has also been demonstrated in malignant melanoma, but not in other benign skin lesions, which has raised the possibility of using it as a predictive and prognosis marker. Its relationship with sentinel lymph node biopsy, however, has not been explored yet. A retrospective study including 120 histological samples of patients diagnosed with malignant cutaneous melanoma in Granada, between 2012 and 2018, was developed. All patients had had a sentinel lymph node biopsy (SLNB) performed at Hospital Universitario San Cecilio. IMP3 immunostaining was simultaneously carried out in the cutaneous lesion. We observed a significant difference regarding the percentage of cells expressing IMP3 (29.73 ± 3.81 for negative SLNB vs 44.86 ± 5.91 for positive SLNB, P = .020). Our endpoint calculated according to the ROC curve of 35% was significant with P = .007. H (P = .013) and AR (P = .016) indexes, created by the percentage of positive tumor cells and the intensity of the IMP3 expression, were also statistically significant. The most optimal cut-off points to predict the positivity of the SLNB were 35 for the percentage of positive tumor cells and 70 for the H score. We found a significant association between the expression of IMP3 and the regional nodal status defined by the SLNB on malignant melanomas in our series.