Plasma microRNA-320a as a Potential Biomarker of Physiological Changes during Training in Professional Volleyball Players

A deeper insight into the mechanisms responsible for athlete performance that may serve as specific and detailed training indicators is still desired, because conventionally used biomarkers provide limited information about the adaptive processes that occur during exercise. The objective of our study was to assess insulin-like growth factor 1 receptors (IGF1R) gene expression and evaluate plasma concentration of selected microRNAs (miRNAs) during a 10-week training period (sampling times: week 1, 4, 7, and 10) in a group of 12 professional female volleyball players. Circulating miRNAs (miR-223, miR-320a, and miR-486) with established concentration in plasma and documented association with the IGF1 signaling pathway, which is involved in muscle development and recovery, were tested. The levels of analyzed miRNAs, tested by one-way ANOVA, were significantly different between four training periods during a 10-week training cycle (miR-223 p < 0.0001, miR-320a p = 0.00021, miR-486 p = 0.0037, respectively). The levels of IGF1R also appeared to be different (p = 0.00092), and their expression showed a trend to increase between the first and third periods. In the fourth period, the expression decreased, although it was higher compared with the baseline. Correlations between concentration levels of miR-223 and miR-320a (rs = 0.54, p < 0.001), as well as between miR-320a and miR-486 (rs = 0.73, p < 0.001) were also found. In the fourth period, a negative correlation between miR-223 plasma level and leucocyte IGF1R expression was found (rs = −0.63, p = 0.028). Multiple linear regression analysis showed that miR-320a (p = 0.024) and creatine kinase (p = 0.028) had the greatest impact on the expression levels of the IGF1R gene. Future studies are required to define whether these miRNAs, especially miR-320a, as well as IGF1R expression could be useful biomarkers of physiological changes during exercise and to discover their detailed biological roles in mode-specific exercise training adaptations of professional athletes.

Expression of Insulin-like Growth Factor Type 1 Receptor is Linked to Inflammation in Adamantinomatous Craniopharyngioma

Introduction Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. Methods We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. Results Patients in the IGF1R high expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate and lower progression-free survival. Beta-catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell–like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein, and decreased the transcription level of interleukin-6. Conclusions High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor cell stem-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. Insulin-like growth factor type 1 receptor plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.

Insulin Receptor in Pancreatic Cancer—Crown Witness in Cross Examination

Background: The proximity of pancreatic cancer (PDAC) to the physiological source of the growth promoting hormone insulin might be exploited by this highly malignant cancer entity. We investigated if (I) PDACs express the insulin receptor (IR) in cancer cells and cancer vasculature, (II) if IR correlates with clinicopathological patient characteristics, including survival, and hence is involved in PDAC biology, (III) if IR is already expressed in precursor lesions, if (IV) the IGF1 receptor (IGF1R) is associated with clinicopathological patient characteristics and survival and (V) is linked to IR expression. Methods: 160 PDAC samples were examined for IR and IGF1R expression by immunohistochemistry. A modified HistoScore was correlated with clinicopathological characteristics and survival. Results: IR overexpression was already observed in pancreatic intraepithelial neoplasia. Furthermore, it was more frequently observed in advanced disease and associated with distant metastasis, UICC stage, lymphatic invasion and an increased lymph node ratio, but without impacting survival in the end. IGF1R expression was not associated with clinicopathological parameters or survival, in contrast to former paradigms. Conclusions: We hypothesize that the close proximity to the pancreatic islets might be advantageous for cancer growth at first, but it experiences self-limitation due to surgical removal or local destruction following accelerated cancer growth.

Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma

(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways.

PSPC1 Potentiates IGF1R Expression to Augment Cell Adhesion and Motility

Paraspeckle protein 1 (PSPC1) overexpression in cancers is known to be the pro-metastatic switch of tumor progression associated with poor prognosis of cancer patients. However, the detail molecular mechanisms to facilitate cancer cell migration remain elusive. Here, we conducted integrated analysis of human phospho-kinase antibody array, transcriptome analysis with RNA-seq, and proteomic analysis of protein pulldown to study the molecular detail of PSPC1-potentiated phenotypical transformation, adhesion, and motility in human hepatocellular carcinoma (HCC) cells. We found that PSPC1 overexpression re-assembles and augments stress fiber formations to promote recruitment of focal adhesion contacts at the protruding edge to facilitate cell migration. PSPC1 activated focal adhesion-associated kinases especially FAK/Src signaling to enhance cell adhesion and motility toward extracellular matrix (ECM). Integrated transcriptome and gene set enrichment analysis indicated that PSPC1 modulated receptor tyrosine kinase IGF1R involved in the focal adhesion pathway and induction of diverse integrins expression. Knockdown IGF1R expression and treatment of IGF1R inhibitor suppressed PSPC1-induced cell motility. Interestingly, knockdown PSPC1-interacted paraspeckle components including NONO, FUS, and the lncRNA Neat1 abolished PSPC1-activated IGF1R expression. Together, PSPC1 overexpression induced focal adhesion formation and facilitated cell motility via activation of IGF1R signaling. PSPC1 overexpression in tumors could be a potential biomarker of target therapy with IGF1R inhibitor for improvement of HCC therapy.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.