Oncogenic role of FOXM1 in human prostate cancer (Review).

Prostate cancer is the leading cause of cancer­related mortality among men worldwide. In particular, castration­resistant prostate cancer presents a formidable clinical challenge and emphasizes the need to develop novel therapeutic strategies. Forkhead box M1 (FOXM1) is a multifaceted transcription factor that is implicated in the acquisition of the multiple cancer hallmark capabilities in prostate cancer cells, including sustaining proliferative signaling, resisting cell death and the activation of invasion and metastasis. Elevated FOXM1 expression is frequently observed in prostate cancer, and in particular, FOXM1 overexpression is closely associated with poor clinical outcomes in patients with prostate cancer. In the present review, recent advances in the understanding of the oncogenic role of deregulated FOXM1 expression in prostate cancer were highlighted. In addition, the molecular mechanisms by which FOXM1 regulates prostate cancer development and progression were described, thereby providing knowledge and a conceptual framework for FOXM1. The present review also provided valuable insight into the inherent challenges associated with translating biomedical knowledge into effective therapeutic strategies for prostate cancer.

Cyclosporin A inhibits prostate cancer growth through suppression of E2F8 transcription factor in a MELK­dependent manner.

The treatment of advanced prostate cancer remains a formidable challenge due to the limited availability of effective treatment options. Therefore, it is imperative to identify promising druggable targets that provide substantial clinical benefits and to develop effective treatment strategies to overcome therapeutic resistance. Cyclosporin A (CsA) showed an anticancer effect on prostate cancer in cultured cell and xenograft models. E2F8 was identified as a master transcription factor that regulated a clinically significant CsA specific gene signature. The expression of E2F8 increased during prostate cancer progression and high levels of E2F8 expression are associated with a poor prognosis in patients with prostate cancer. MELK was identified as a crucial upstream regulator of E2F8 expression through the transcriptional regulatory network and Bayesian network analyses. Knockdown of E2F8 or MELK inhibited cell growth and colony formation in prostate cancer cells. High expression levels of E2F8 and androgen receptor (AR) are associated with a worse prognosis in patients with prostate cancer compared with low levels of both genes. The inhibition of E2F8 improved the response to AR blockade therapy. These results suggested that CsA has potential as an effective anticancer treatment for prostate cancer, while also revealing the oncogenic role of E2F8 and its association with clinical outcomes in prostate cancer. These results provided valuable insight into the development of therapeutic and diagnostic approaches for prostate cancer.

Emerging role of E2F8 in human cancer.

E2F8 is a multifaceted transcription factor that plays a crucial role in mediating the hallmarks of cancer, including sustaining proliferative signaling, resisting cell death, and activating invasion and metastasis. Aberrant E2F8 expression is associated with poor clinical outcomes in most human cancers. However, E2F8 also exhibits tumor-suppressing activity; thus, the role of E2F8 in cell-fate determination is unclear. In this review, we highlight the recent progress in understanding the role of E2F8 in human cancers, which will contribute to building a conceptual framework and broadening our knowledge pertaining to E2F8. This review provides insight into future challenges and perspectives regarding the translation of biological knowledge into therapeutic strategies for the treatment of cancer.

Crizotinib attenuates cancer metastasis by inhibiting TGFß signaling in non-small cell lung cancer cells.

Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFß signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFß receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFß- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFß signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.

Mandibular Stability After Sagittal Split Ramus Osteotomy With Hybrid Technique in Asymmetric Patients.

ABSTRACT: The hybrid technique after bilateral sagittal split ramus osteotomy is an internal fixation method using monocortical mini-plates and additional bicortical positional screws. In this study, we analyzed the postoperative stability of 23 patients with mandibular asymmetry who underwent bilateral sagittal split ramus osteotomy and hybrid fixation with or without LeFort I osteotomy. Anatomical landmarks of the deviated and non-deviated sides of the jaw were established to measure the angle and distance to the reference plane in three-dimensional cone beam computed tomography images. We analyzed the positional changes and correlations of the reference points at preoperative (T1), postoperative 2 weeks (T2), and postoperative 1 year (T3). There were significant differences in preoperative position of the upper and lower molar cervix alveolar crest to the reference plane (U6-X and L6-X) and the condylion angles between deviated and non-deviated sides. Postoperatively (T2-T3), each reference point had no statistically significant positional change. Pearson correlation coefficient between the amount of menton deviation (ME-X at T1) and positional change of menton after surgery (T2-T3) was 0.30, and P value was 0.168. The hybrid fixation technique is an effective fixation method for achieving postoperative stability for mandibular asymmetry.

Osteogenesis imperfecta and combined orthodontics and orthognathic surgery: a case report on two siblings.

Osteogenesis imperfecta is a heterogeneous group of connective tissue diseases that is predominantly characterized by bone fragility and skeletal deformity. Two siblings with undiagnosed type I osteogenesis imperfecta underwent orthognathic surgery for the treatment of facial asymmetry and mandibular prognathism. The authors report two cases of combined orthodontics and orthognathic surgery in patients with type I osteogenesis imperfecta, mandibular prognathism, and facial asymmetry.

Altered expression of fucosylation pathway genes is associated with poor prognosis and tumor metastasis in non­small cell lung cancer.

Fucosylation is a post­translational modification that attaches fucose residues to protein­ or lipid­bound oligosaccharides. Certain fucosylation pathway genes are aberrantly expressed in several types of cancer, including non­small cell lung cancer (NSCLC), and this aberrant expression is associated with poor prognosis in patients with cancer. However, the molecular mechanism by which these fucosylation pathway genes promote tumor progression has not been well­characterized. The present study analyzed public microarray data obtained from NSCLC samples. Multivariate analysis revealed that altered expression of fucosylation pathway genes, including fucosyltransferase 1 (FUT1), FUT2, FUT3, FUT6, FUT8 and GDP­L­fucose synthase (TSTA3), correlated with poor survival in patients with NSCLC. Inhibition of FUTs by 2F­peracetyl­fucose (2F­PAF) suppressed transforming growth factor ß (TGFß)­mediated Smad3 phosphorylation and nuclear translocation in NSCLC cells. In addition, wound­healing and Transwell migration assays demonstrated that 2F­PAF inhibited TGFß­induced NSCLC cell migration and invasion. Furthermore, in vivo bioluminescence imaging analysis revealed that 2F­PAF attenuated the metastatic capacity of NSCLC cells. These results may help characterize the oncogenic role of fucosylation in NSCLC biology and highlight its potential for developing cancer therapeutics.

The conflicting role of E2F1 in prostate cancer: A matter of cell context or interpretational flexibility?

The transcription factor E2F1 plays a crucial role in mediating multiple cancer hallmark capabilities that regulate cell cycle, survival, apoptosis, metabolism, and metastasis. Aberrant activation of E2F1 is closely associated with a poor clinical outcome in various human cancers. However, E2F1 has conflictingly been reported to exert tumor suppressive activity, raising a question as to the nature of its substantive role in the control of cell fate. In this review, we summarize deregulated E2F1 activity and its role in prostate cancer. We highlight the recent advances in understanding the molecular mechanism by which E2F1 regulates the development and progression of prostate cancer, providing insight into how cell context or data interpretation shapes the role of E2F1 in prostate cancer. This review will aid in translating biomedical knowledge into therapeutic strategies for prostate cancer.

Identification of phospholipase C ß downstream effect on transient receptor potential canonical 1/4, transient receptor potential canonical 1/5 channels.

Gαq-coupled receptor stimulation was implied in the activation process of transient receptor potential canonical (TRPC)1/4 and TRPC1/5 heterotetrameric channels. The inactivation occurs due to phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) depletion. When PI(4,5)P2 depletion was induced by muscarinic stimulation or inositol polyphosphate 5-phosphatase (Inp54p), however, the inactivation by muscarinic stimulation was greater compared to that by Inp54p. The aim of this study was to investigate the complete inactivation mechanism of the heteromeric channels upon Gαq-phospholipase C ß (Gαq-PLCß) activation. We evaluated the activity of heteromeric channels with electrophysiological recording in HEK293 cells expressing TRPC channels. TRPC1/4 and TRPC1/5 heteromers undergo further inhibition in PLCß activation and calcium/protein kinase C (PKC) signaling. Nevertheless, the key factors differ. For TRPC1/4, the inactivation process was facilitated by Ca2+ release from the endoplasmic reticulum, and for TRPC1/5, activation of PKC was concerned mostly. We conclude that the subsequent increase in cytoplasmic Ca2+ due to Ca2+ release from the endoplasmic reticulum and activation of PKC resulted in a second phase of channel inhibition following PI(4,5)P2 depletion.

Transcription factor ZFHX3 regulates calcium influx in mammary epithelial cells in part via the TRPV6 calcium channel.

Zinc finger homeobox 3 (ZFHX3) is a transcription factor that regulates multiple cellular processes including cell proliferation, differentiation and neoplastic development. It is also involved in the function of steroid hormones estrogen and progesterone and the peptide hormone prolactin in mammary epithelial cells. In this study, we investigated whether and how ZFHX3 regulates intracellular calcium homeostasis in mammary epithelial cells. We found that ZFHX3 affected both store operated calcium entry and store independent calcium entry (SOCE and SICE). Simultaneously, the expression of the calcium channel TRPV6 was regulated by ZFHX3, as demonstrated by expression analysis and luciferase reporter assay. In cells with knockdown of ZFHX3, calcium entry was partially rescued by the overexpression of wild type but not the pore mutants of TRPV6. In addition, overexpression of TRPV6 promoted differentiation of the MCF10A mammary epithelial cells in three-dimensional culture, which is consistent with our previous findings that ZFHX3 is essential for mammary gland differentiation. These findings suggest that ZFHX3 plays an important role in intracellular calcium homeostasis in mammary epithelial cells, at least in part, by regulating TRPV6.

PI3K pathway in prostate cancer: All resistant roads lead to PI3K.

The phosphoinositide 3-kinase (PI3K) pathway integrates multifarious environmental cues to regulate cell survival, growth, and metabolism. Hyperactivation of the PI3K pathway increases biological fitness by offering a high degree of adaptability to and resilience against diverse perturbations, thus conferring survival benefits on premalignant and transformed cells. In prostate cancer, the PI3K pathway is aberrantly activated by various genetic and epigenetic alterations and its hyperactivation is closely associated with a poor clinical outcome. In this review, we discuss the challenges encountered with clinically effective therapies targeting the PI3K pathway in prostate cancer, highlighting the clinical importance of combination therapies. In particular, we address how prostate cancer cells utilize the PI3K pathway for the development of resistance to a broad range of anticancer treatments. In addition, we describe the molecular mechanisms by which prostate cancer cells become resistant to PI3K pathway inhibitors. This review will be helpful in translating biological knowledge into therapeutic strategies for the treatment of prostate cancer and provide insight into overcoming therapeutic challenges associated with prostate cancer.

Geraniol suppresses prostate cancer growth through down-regulation of E2F8.

Geraniol, an acyclic dietary monoterpene, has been found to suppress cancer survival and growth. However, the molecular mechanism underlying the antitumor action of geraniol has not been investigated at the genome-wide level. In this study, we analyzed the microarray data obtained from geraniol-treated prostate cancer cells. Geraniol potently altered a gene expression profile and primarily down-regulated cell cycle-related gene signatures, compared to linalool, another structurally similar monoterpene that induces no apparent phenotypic changes. Master regulator analysis using the prostate cancer-specific regulatory interactome identified that the transcription factor E2F8 as a specific target molecule regulates geraniol-specific cell cycle signatures. Subsequent experiments confirmed that geraniol down-regulated E2F8 expression and the knockdown of E2F8 was sufficient to suppress cell growth by inducing G2 /M arrest. Epidemiological analysis showed that E2F8 is up-regulated in metastatic prostate cancer and associated with poor prognosis. These results indicate that E2F8 is a crucial transcription regulator controlling cell cycle and survival in prostate cancer cells. Therefore, our study provides insight into the role of E2F8 in prostate cancer biology and therapeutics.

Dental implant treatment after healing of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in the same region: a case report.

Although pathophysiology, incidence, and factors associated with the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and management strategies for patients treated with bisphosphonates or patients with BRONJ are well-established, few guidelines or recommendations are available for patients with a history of successfully healed BRONJ. We present a case of successful dental implant treatment after healing of BRONJ in the same region of the jaw, and speculate that implant placement is possible after healing of BRONJ surgery in select cases.

Influence of anatomic position and intraoperative exposure of the inferior alveolar nerve on neurosensory disturbance after sagittal split ramus osteotomy: a three-dimensional computed tomography study.

OBJECTIVE: To evaluate the influence of the anatomic position and intraoperative exposure of the inferior alveolar nerve on neurosensory disturbance (NSD) in sagittal split ramus osteotomy. STUDY DESIGN: The anatomic factors of the nerve were measured on preoperative three-dimensional computed tomography in 98 patients. The intraoperative nerve exposure was assessed. NSD was evaluated for 1 year after surgery. The correlations between NSD and the factors were analyzed. RESULTS: The NSD decreased as the lateral marrow space from the nerve increased (P < .01). The complete nerve exposure increased NSD by 7.6 times (P = .01). The nerve exposure increased as the buccal plate thickness increased (P = .01) and decreased as the vertical marrow space from the nerve increased (P = .01). CONCLUSIONS: The nerve exposure and the lateral marrow space from the nerve affected NSD. The buccal plate thickness and the vertical marrow space indirectly affected NSD through nerve exposure.

The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review).

Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation.

Data-driven Analysis of TRP Channels in Cancer: Linking Variation in Gene Expression to Clinical Significance.

BACKGROUND: Experimental evidence has suggested that transient receptor potential (TRP) channels play a crucial role in tumor biology. However, clinical relevance and significance of TRP channels in cancer remain largely unknown. MATERIALS AND METHODS: We applied a data-driven approach to dissect the expression landscape of 27 TRP channel genes in 14 types of human cancer using International Cancer Genome Consortium data. RESULTS: TRPM2 was found overexpressed in most tumors, whereas TRPM3 was broadly down-regulated. TRPV4 and TRPA1 were found up- and down-regulated respectively in a cancer type-specific manner. TRPC4 was found to be closely associated with incidence of head and neck cancer and poor survival of patients with kidney cancer. TRPM8 was identified as a new molecular marker for lung cancer diagnosis and TRPP1 for kidney cancer prognosis. CONCLUSION: Our data-driven approach demonstrates that the variation in the expression of TRP channel genes is manifested across various human cancer types and genes, for certain TRP channels have strong predictive diagnostic and prognostic potential.

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids.

Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.

Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.