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Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01090-x.

Mechanical features of cancer cells emerge as a distinct trait during development and progression of solid tumors. Herein, we discuss recent key findings regarding the impact of various types of mechanical stresses on cancer cell properties. Data suggest that different mechanical forces, alterations of matrix rigidity and tumor microenvironment facilitate cancer hallmarks, especially invasion and metastasis. Moreover, a subset of mechanosensory proteins are responsible for mediating mechanically induced oncogenic signaling and response to chemotherapy. Delineating cancer dynamics and decoding of respective signal transduction mechanisms will provide new therapeutic strategies against solid tumors in the future.

Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology‐related mechanisms of craniosynostosis still remain unknown. Understanding how aberrant mechanosensation and mechanotransduction drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage and prevent premature suture fusion. Herein, we provide evidence for the first time on the role of polycystin‐1 (PC1), a key protein in cellular mechanosensitivity, in craniosynostosis, using primary cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, two common types of craniosynostosis. Initially, we showed that PC1 is expressed at the mRNA and protein level in both trigonocephaly and dolichocephaly cranial suture cells. Followingly, by utilizing an antibody against the mechanosensing extracellular N‐terminal domain of PC1, we demonstrated that PC1 regulates runt‐related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via extracellular signal–regulated kinase (ERK) signalling in our human craniosynostosis cell model. Altogether, our study reveals a novel mechanotransduction signalling axis, PC1‐ERK‐RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients.

Craniosynostosis is the premature fusion of skull sutures and has a severe pathological impact on childrens' life. Mechanical forces are capable of triggering biological responses in bone cells and regulate osteoblastogenesis in cranial sutures, leading to premature closure. The mechanosensitive proteins polycystin-1 (PC1) and polycystin-2 (PC2) have been documented to play an important role in craniofacial proliferation and development. Herein, we investigated the contribution of PC1 to the pathogenesis of non-syndromic craniosynostosis and the associated molecular mechanisms. Protein expression of PC1 and PC2 was detected in bone fragments derived from craniosynostosis patients via immunohistochemistry. To explore the modulatory role of PC1 in primary cranial suture cells, we further abrogated the function of PC1 extracellular mechanosensing domain using a specific anti-PC1 IgPKD1 antibody. Effect of IgPKD1 treatment was evaluated with cell proliferation and migration assays. Activation of PI3K/AKT/mTOR pathway components was further detected via Western blot in primary cranial suture cells following IgPKD1 treatment. PC1 and PC2 are expressed in human tissues of craniosynostosis. PC1 functional inhibition resulted in elevated proliferation and migration of primary cranial suture cells. PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis.

The mechanobiological aspects of glioblastoma (GBM) pathogenesis are largely unknown. Polycystin-1 (PC1) is a key mechanosensitive protein which perceives extracellular mechanical cues and transforms them into intracellular biochemical signals that elicit a change in cell behaviour. The aim of the present study was to investigate if and how PC1 participates in GBM pathogenesis under a mechanically induced microenvironment. Therefore, we subjected T98G GBM cells to continuous hydrostatic pressure (HP) and/or PC1 blockade and evaluated their effect on cell behaviour, the activity of signalling pathways and the expression of mechano-induced transcriptional regulators and markers associated with properties of cancer cells. According to our data, PC1 and HP affect GBM cell proliferation, clonogenicity and migration; the diameter of GBM spheroids; the phosphorylation of mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK); the protein expression of transcription cofactors YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ); and the mRNA expression of markers related to anti-apoptosis, apoptosis, angiogenesis, epithelial to mesenchymal transition (EMT) and proliferation. Together, our in vitro results suggest that PC1 plays an important role in GBM mechanobiology.

Anti-SARS-CoV-2 spike RBD (receptor-binding domain) IgG antibody levels were monitored in 1643 volunteer healthcare workers of Eginition, Evangelismos, and Konstantopoulio General Hospitals (Athens, Greece), who underwent vaccination with two doses of COVID-19 BNT162b2 mRNA vaccine (Pfizer) and had no history of SARS-CoV-2 infection. Venous blood was collected 20–30 days after the second vaccine dose and anti-RBD IgG levels were determined using CMIA SARS-CoV-2 IgG II Quant (Abbott) on ARCHITECT i System or ADVIA Centaur SARS-CoV-2 IgG (Siemens) on Centaur XP platform. From the total population of 1643 vaccinees (533 M/1110 F; median age = 49; interquartile range-IQR = 40–56), 1636 (99.6%) had anti-SARS-CoV-2 IgG titers above the positivity threshold of the assay used. One-Way ANOVA Kruskal-Wallis H test showed a statistically significant difference in the median of antibody titers between the different age groups (p < 0.0001). Consistently, Spearman’s correlation coefficient (r) for IgGs and age as continuous variables was −0.2380 (p = 1.98 × 10−17). Moreover, antibody titers were slightly higher by 1.2-mean fold (p = 3 × 10−6) in the total female population of the three hospitals (median = 1594; IQR = 875–2584) as compared to males (median = 1292; IQR = 671.9–2188). The present study supports that BNT162b2 vaccine is particularly effective in producing high anti-SARS-CoV-2 IgG levels in healthy individuals, and this humoral response is age- and gender-dependent.

Polycystic Kidney Disease (PKD), which is attributable to mutations in the PKD1 and PKD2 genes encoding polycystin‐1 (PC1) and polycystin‐2 (PC2) respectively, shares common cellular defects with cancer, such as uncontrolled cell proliferation, abnormal differentiation and increased apoptosis. Interestingly, PC1 regulates many signalling pathways including Jak/STAT, mTOR, Wnt, AP‐1 and calcineurin‐NFAT which are also used by cancer cells for sending signals that will allow them to acquire and maintain malignant phenotypes. Nevertheless, the molecular relationship between polycystins and cancer is unknown. In this study, we investigated the role of PC1 in cancer biology using glioblastoma (GOS3), prostate (PC3), breast (MCF7), lung (A549) and colorectal (HT29) cancer cell lines. Our in vitro results propose that PC1 promotes cell migration in GOS3 cells and suppresses cell migration in A549 cells. In addition, PC1 enhances cell proliferation in GOS3 cells but inhibits it in MCF7, A549 and HT29 cells. We also found that PC1 up‐regulates mTOR signalling and down‐regulates Jak signalling in GOS3 cells, while it up‐regulates mTOR signalling in PC3 and HT29 cells. Together, our study suggests that PC1 modulates cell proliferation and migration and interacts with mTOR and Jak signalling pathways in different cancer cell lines. Understanding the molecular details of how polycystins are associated with cancer may lead to the identification of new players in this devastating disease.

Psoriatic plaques tend to localize to the knees and elbows, areas that are particularly subject to mechanical stress resulting from bending and friction. Moreover, plaques often develop at sites of mechanical trauma or injury (Koebner phenomenon). Nevertheless, mechanotransduction has never been linked to psoriasis. Polycystins (polycystin-1, PC1; polycystin-2, PC2) are mechanosensitive molecules that function as key regulators of cellular mechanosensitivity and mechanotransduction. The aim of this in vitro study was to investigate the role of polycystins in the development of psoriasis. We showed that PC1 knockdown in HaCaT cells led to an elevated mRNA expression of psoriasis-related biomarkers Ki-67, IL-6, TNF-α, VEGF and Bcl-2, while PC1 functional inhibition was accompanied by increased cell proliferation and migration of HaCaT cells. In addition, PC1 knockdown via siRNA in HaCaT cells was followed by activation of critical molecules of the mTOR and MAPK pathways and this mTOR pathway activation was ERK-dependent. Furthermore, loss of PC1 protein expression and elevated levels of activated mTOR substrates were also observed in human samples of psoriatic plaques. Overall, our study suggests that the PC1/ERK/mTOR signaling axis represents a novel potential mechanism in psoriasis pathogenesis.

Background To investigate the association between frailty, Parkinson’s disease (PD), and the probability of prodromal Parkinson’s disease (prodromal PD) in Greek community-dwelling older individuals. Methods Parkinson’s disease diagnosis was reached through standard clinical research procedures. Probability of prodromal PD was calculated according to the International Parkinson and Movement Disorder Society’s research criteria for PD-free participants. Frailty was evaluated according to definitions of the phenotypic and multidomain approach. Logistic and linear regression models were performed to investigate associations between frailty (predictor) and the probability of prodromal PD, either continuous or dichotomous (≥30% probability score), or PD (outcome). Results Data from 1765 participants aged 65 and older were included in the present analysis. Parkinson’s disease and prodromal PD prevalence were 1.9% and 3.0%, respectively. Compared to nonfrail participants, those who were frail, as identified with either the Fried frailty phenotype or Frailty Index had approximately 4 (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.54–10.89) and 12 times (OR 12.16, 95% CI 5.46–27.09) higher odds of having a PD diagnosis, respectively. Moreover, compared to the nonfrail, frail participants as identified with either the Fried frailty phenotype or Frailty Index had 2.8 (OR 2.83, 95% CI 1.09–7.37) and 8.3 times (OR 8.39, 95% CI 4.56–15.42) higher odds of having possible/probable prodromal PD, respectively. Conclusions Frailty status was associated with prodromal PD and PD, suggesting common characteristics or underlying mechanisms of these conditions. Although prospective studies are warranted, acknowledging the possible association of frailty, PD, and prodromal PD may improve their clinical management.

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.

Alterations in the process of mechanotransduction have been implicated in the pathogenesis of several diseases such as genetic diseases, osteoporosis, cardiovascular anomalies, and cancer. Several studies over the past twenty years have demonstrated that polycystins (polycystin-1, PC1; and polycystin-2, PC2) respond to changes of extracellular mechanical cues, and mediate pathogenic mechanotransduction and cyst formation in kidney cells. However, recent reports reveal the emergence of polycystins as key proteins that facilitate the transduction of mechano-induced signals in various clinical entities besides polycystic kidney disease, such as cancer, cardiovascular defects, bone loss, and deformations, as well as inflammatory processes like psoriasis. Herewith, we discuss data from recent studies that establish this role with potential clinical utility.

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation.

Membrane receptors constitute novel targets during current treatment of metastatic colorectal cancer (CRC) due to the fact that their aberrant expression/activity favors cancer cell properties. Protein trafficking is responsible for the correct targeting of membrane receptors to the apical and basolateral surfaces, as well as to the adherent and tight junctions of the cell. Impaired availability or distribution of these receptors along the plasma membrane is not only associated with defective cellular homeostasis and tumor progression, but also to emerging mechanisms of resistance to CRC-targeted therapy. The present review describes how protein trafficking facilitates invasion and metastasis of CRC cells and focuses on receptor tyrosine kinases (RTKs) endocytic transport, providing thoughts for surpassing RTKs-centered mechanisms of resistance.

BACKGROUND Pediatric brain tumors are characterized by altered epigenetic profiles and deregulated chromatin remodelling that affects gene expression. Histone lysine methylation has emerged as important chromatin function regulator, with potential role in glioma formation. Τhis study investigates the expression of histone lysine methyltransferases (SETDB1, SUV39H1, EZH2, MLL2, SETD2) and their corresponding methylation marks (H3K9me3, H3K27me3, H3K4me2/3, H3K36me3) in pediatric astrocytomas. MATERIAL AND METHODS Thirty-four (34) archival pediatric astrocytomas [27 low grade (I/II) and 7 high grade (III/IV) tumors; 21 males, 13 females; 1–15 years old] and 5 postmortem normal brain samples were studied. Methyltransferases expression and histone marks were detected by immunohistochemistry as H-score (intensity multiplied with cell percentage, 0–300) and validated by western blot. RESULTS Elevated nuclear SETD2 and SETDB1 staining was observed in all astrocytomas (median H-score:165 and 110, respectively). SETDB1 and SETD2 expression levels were positively associated (p=0.004), being higher in high grade compared to lower grade tumors (p=0.001, p=0.027, respectively). Furthermore, SETDB1 staining was significantly increased in male children (p=0.051) and negatively associated with patients age (p=0.028). A moderate nuclear and cytoplasmic staining was obtained for MLL2 at low grade (median H-score:84) compared to high grade tumors (median H-score:144). In accordance, lower SUV39H1 nuclear and cytoplasmic expression was detected in low grade tissues (median H score:85) compared to high grade (median H-score:160). EZH2 presented no significant nuclear expression. Increased nuclear staining of H3K9me3 and H4K20me3 repressive marks was observed in astrocytomas (median H-score:297 and 270, respectively), being positively associated (p=0.02). Elevated nuclear staining of H3K4me3 active mark (median H-score:210) was detected in astrocytomas, being significantly higher in high grade tumors (p=0.025) and in male children (p=0.036). CONCLUSION SETDB1, SETD2, SUV39H1 and MLL2 may play a significant role in modulating gene expression in pediatric astrocytomas. Increased presence of H3K9me3, H4K20me3 and H3K4me3 histone marks signifies their possible participation in gliomagenesis. Larger cohort studies need to elucidate the functional significance and underlying molecular mechanisms of these chromatin-modifying enzymes and respective histone changes in pediatric astrocytomas.

Src has been one of the most studied proto-oncogenes. The cellular Src (c-Src) holds a critical role in several human malignancies and has emerged as a key factor that promotes tumor progression during the multistep process of colorectal cancer (CRC) pathogenesis. The robust activation of Src in CRC of aggressive phenotype and poor prognosis seems to be a subsequent event of a strong link between its deregulated activity and the tumor's cell adhesion properties, invasiveness and metastatic potential. The rarely detected genetic defects drive interest in signaling networks that control Src kinase activity and integrate the association of Src with receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). Therefore, a dynamic crosstalk is being formed with oncogenic capacity and therapeutic applications, because Src inhibition seems to sensitize previously unresponsive cancer cells to chemotherapy and anti-EGFR inhibitors. The present review explores the molecular basis behind Src inhibition in colorectal carcinomas. Furthermore, preclinical studies and clinical trials of Src inhibitors and combination regimens are discussed, providing new insights for further investigation and new therapeutic strategies.

Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation. Primary osteoblast-like PC1-expressing cells subjected to mechanical-stretching exhibited a PC1-dependent increase of the phosphorylated(p)/active form of JAK2. Specific interaction of PC1-CT with pJAK2 was observed after stretching while pre-treatment of cells with PC1 (anti-IgPKD1) and JAK2 inhibitors abolished JAK2 activation. Consistently, mechanostimulation triggered PC1-mediated phosphorylation and nuclear translocation of STAT3. The nuclear phosphorylated(p)/DNA-binding competent pSTAT3 levels were augmented after stretching followed by elevated DNA-binding activity. Pre-treatment with a STAT3 inhibitor either alone or in combination with anti-IgPKD1 abrogated this effect. Moreover, PC1-mediated mechanostimulation induced elevation of Runx2 mRNA levels. ChIP assays revealed direct regulation of Runx2 promoter activity by STAT3/Runx2 after mechanical-stretching that was PC1-dependent. Our findings show that mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation.

Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-κB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.

Background Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients’ survival. Methods We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. Results CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients’ cohort. Conclusions We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance.

Transient receptor potential (TRP) channels are cation channels which act as molecular sensors that enable cells to detect and respond to a plethora of mechanical and environmental cues. TRPs are involved in various physiological processes, such as mechanosensation, non-inception and thermosensation, while mutations in genes encoding them can lead to pathological conditions, called “channelopathies”. The subfamily of transient receptor potential polycystins (TRPPs), Polycystin 1 (PC1, TRPP1) and Polycystin 2 (PC2, TRPP2), act as mechanoreceptors, sensing external mechanical forces, including strain, stretch and fluid shear stress, triggering a cascade of signaling pathways involved in osteoblastogenesis and ultimately bone formation. Both in vitro studies and research on animal models have already identified their implications in bone homeostasis. However, uncertainty veiling the role of polycystins (PCs) in bone disease urges studies to elucidate further their role in this field. Mutations in TRPPs have been related to autosomal polycystic kidney disease (ADKPD) and research groups try to identify their role beyond their well-established contribution in kidney disease. Such an elucidation would be beneficial for identifying signaling pathways where polycystins are involved in bone diseases related to exertion of mechanical forces such as osteoporosis, osteopenia and craniosynostosis. A better understanding of the implications of TRPPs in bone diseases would possibly lay the cornerstone for effective therapeutic schemes.

Background/purpose Polycystins 1 and 2 (PC-1 and PC-2) constitute a family of cellular proteins detected in a variety of epithelial cells throughout human tissues. They function as mechanosensors and contribute to cellular homeostasis through proliferation, differentiation and apoptotic processes. Nevertheless, their fundamental role in cell-to-cell mechanical interactions, cell–matrix communication, tissue morphogenesis and planar cell polarity connote their engagement in processes of oncogenesis, including invasion and metastasis. The aim of the study was to investigate the expression of PC-1 and PC-2 in colorectal cancer (CRC), identify possible correlations with histopathological characteristics and explore the underpinning signal transduction mechanisms. Methods The immunohistochemical expression of PC-1 and PC-2 was evaluated in paraffin sections of 144 CRC patients and the results were statistically correlated with clinical and pathologic parameters. Molecular mechanisms were explored by Western blot, immunofluorescence and flow cytometry in SW480 CRC cell line expressing PC-1 and PC-2. Results Significantly elevated cytoplasmic expression was observed for PC-1 and PC-2 in mucinous carcinomas (p = 0.0035 and p = 0.0001, respectively). High expression levels of PC-2 were correlated with advanced TNM stage (p = 0.0324) and depth of tumour invasion (p = 0.0311). High expression levels of PC-1 (p = 0.0078) and altered expression levels of PC-2 in the transition zone from normal to cancerous tissue (p = 0.0198) were associated with reduced five-year survival rate. Altered expression of PC-1 in the transition zone was correlated with higher chance of relapse for the patients (p = 0.0019). Experiments in SW480 cells revealed funneling of PC-1 and PC-2 function via mammalian target of rapamycin (mTOR) and p70S6 kinases. Conclusions Our findings suggest that PC-1 and PC-2 are implicated in the development of an aggressive phenotype in CRC, as well as in reduced five-year survival rate and cancer-free survival, thus constituting potential prognostic markers. Their function seems to be partially mediated by key molecules of the mTOR signaling pathway. Disclosure All authors have declared no conflicts of interest.