The purpose of this study was to investigate the effects of BOC on glioblastoma cells and its underlying mechanisms. In vitro, BOC-knockdown was performed in glioma cell lines. CCK-8 and Transwell were used to assess the impact of BOC on the viability, invasion, and migration of gliobma cells. RNA-seq technology was employed to analyze the differential gene expression between BOC-knockdown glioma cells and the control group, and qRT-PCR was used to validate the expression of downstream differential genes. SMO-overexpression was performed to investigate the effects of SMO on glioma cells. A BOC-knockdown mouse subcutaneous tumor model was to verify the effects of BOC on mouse tumors. Tissue microarray technology was used to detect the expression of BOC and SMO in samples of normal human brain tissue and glioma tissue. In vitro, BOC-knockdown inhibited the viability, invasion, and migration of glioma cells, as well as downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Conversely, SMO-overexpression upregulated the viability, invasion, and migration abilities of BOC-knockdown cells. In vivo, BOC-knockdown suppressed tumor growth in mice and downregulated the expression of downstream differential genes SMO, EGFR, HRAS, and MRAS. Tissue microarray results showed that both BOC and SMO were highly expressed in glioma tissues. BOC is aberrantly overexpressed in glioma patients and promotes glioma development. Mechanistically, BOC activates the Hedgehog (Hh) and RAS signaling pathways by upregulating the expression of SMO, EGFR, HRAS, and MRAS, thereby facilitating the Proliferation, invasion and migration of glioma cells.

Smoothened (Smo) is a critical component regulating the Hedgehog signaling pathway. However, whether Smo is associated with the modulation of olfactory recognition capabilities of bees remains unclear. In this study, we amplified Smo from Apis mellifera. The coding sequence of Smo was 2952 bp long, encoded 983 amino acids. Smo was most highly expressed in the antennae. Cyclopamine (200 μg/mL) significantly reduced but purmorphamine (800 μg/mL) significantly increased Smo expression (p < 0.05). OR152 and OR2 expression in the cyclopamine group significantly decreased, whereas OR152 expression in the purmorphamine group significantly increased (p < 0.05). A significant decrease in the relative values of electroantennography was observed in the cyclopamine group exposed to neral. Behavioral tests indicated a significant decrease in the attractive rates of neral, VUAA1, linalool, and methyl heptenone in the cyclopamine group. Conversely, the selection rates of linalool and methyl heptenone in the purmorphamine group significantly increased. Our findings indicate that Smo may play a role in modulating olfactory receptors in bees.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.

BACKGROUND: Oral cancer poses a significant burden on public health in India, with higher incidence and mortality rates. Despite advancements in treatment modalities, prognosis remains poor due to factors such as localized recurrence and lymph node metastasis, potentially influenced by cancer stem cells. Among signaling pathways implicated in CSC regulation, the Hedgehog pathway plays a crucial role in oral squamous cell carcinoma (OSCC).
METHODS: 97 OSCC patients\' tissue samples were collected and subjected to RNA isolation, cDNA synthesis and quantitative real-time PCR to analyze PTCH1 and SMO expression. Protein expression was assessed through immunohistochemistry. Clinicopathological parameters were correlated with gene and protein expression. Statistical analysis included Pearson chi-square tests, co-relation co-efficient tests, Kaplan-Meier survival analysis and ROC curve analysis.
RESULTS: PTCH1 expression correlated with lymphatic permeation (p = 0.002) and tumor stage (p = 0.002), while SMO expression correlated with lymph node status (p = 0.034) and tumor stage (p = 0.021). PTCH1 gene expression correlated with lymph node status (p = 0.024). High PTCH1 gene expression was associated with shorter survival in tongue cancer patients. ROC curve analysis indicated diagnostic potential for PTCH1 and SMO gene and cytoplasmic SMO expression in distinguishing malignant tissues from adjacent normal tissues.
CONCLUSIONS: PTCH1 and SMO play a crucial role in oral cancer progression, correlating with tumor stages and metastatic potential. Despite not directly influencing overall survival, PTCH1 expression at specific anatomical sites hints at its prognostic implications. PTCH1 and SMO exhibit diagnostic potential, suggesting their utility as molecular markers in oral cancer management and therapeutic strategies.

Meningioma is the most common type of primary brain tumor. Surgical resection followed by surveillance is the first-line treatment for the majority of symptomatic meningiomas; however, recent advances in molecular sequencing, DNA methylation, proteomics, and single-cell sequencing provide insights into further characterizing this heterogeneous group of tumors with a wide range of prognoses. A subset of these tumors are highly aggressive and cause severe morbidity and mortality. Therefore, identifying those individuals with a poor prognosis and intervening are critical. This review aims to help readers interpret the molecular profiling of meningiomas to identify patients with worse prognoses and guide the management and strategy for surveillance.

Multiple cancers have been associated with MYB-related protein B (MYBL2), its involvement in clear cell renal cell carcinoma (ccRCC) has yet to be demonstrated. Our study revealed a significant upregulation of MYBL2 in ccRCC tissues, correlating with clinicopathological features and patient prognosis. Increased MYBL2 expression promoted cell proliferation and suppressed apoptosis. RNA-seq analysis unveiled a reduction in smoothened (SMO) expression upon MYBL2 silencing. However, luciferase and chromatin immunoprecipitation (ChIP) assays demonstrated MYBL2\'s positive regulation of SMO expression by directly targeting the SMO promoter. Reintroduction of SMO expression in MYBL2-knocked down cells partially restored cell proliferation and mitigated apoptosis inhibition. Overall, these results indicate that MYBL2 facilitates ccRCC progression by enhancing SMO expression, suggesting its potential as an intriguing drug target for ccRCC therapy.

Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological setting, it is associated with oncogenesis and is responsible for disease progression and poor clinical outcomes. Hedgehog signaling mediates downstream actions via Glioma Associated Oncogene Homolog (GLI) transcription factors. Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.

The third most prevalent malignancy to cause mortality is hepatocellular carcinoma (HCC). The Hedgehog (Hh) signaling pathway is activated by binding to the transmembrane receptor Patched-1 (PTCH-1), which depresses the transmembrane G protein-coupled receptor Smoothened (SMO). This study was performed to examine the preventative and therapeutic effects of cannabidiol in adult rats exposed to diethyl nitrosamine (DENA)-induced HCC.A total of 50 male rats were divided into five groups of 10 rats each. Group I was the control group. Group II received intraperitoneal (IP) injections of DENA for 14 weeks. Group III included rats that received cannabidiol (CBD) orally (3-30 mg/kg) for 2 weeks and DENA injections for 14 weeks. Group IV rats received oral CBD for 2 weeks before 14 weeks of DENA injections. Group V included rats that received CBD orally for 2 weeks after their last injection of DENA. Measurements were made for alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and alpha fetoprotein (AFP). Following total RNA extraction, Smo, Hhip, Ptch-1, and Gli-1 expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR). A histopathological analysis of liver tissues was performed.The liver enzymes, oxidant-antioxidant state, morphological, and molecular parameters of the adult male rat model of DENA-induced HCC showed a beneficial improvement after CBD administration. In conclusion, by focusing on the Hh signaling system, administration of CBD showed a beneficial improvement in the liver enzymes, oxidant-antioxidant status, morphological, and molecular parameters in the DENA-induced HCC in adult male rats.

BACKGROUND: HERC4 has been reported to have functions in several types of tumors, but its roles in ovarian cancer have not been studied yet.
METHODS: Primary tissues from ovarian cancer patients and cell lines were collected for real-time PCR. Kaplan-Meier Plotter was used to predict the prognosis of ovarian cancer patients. HERC4 was overexpressed in cells by lentivirus, and CCK-8 assay was performed to evaluate cell viability. Real-time PCR and Western blot were carried out to analyze the mRNA and protein expression, respectively. Xenograft tumor models were established to analyze HERC4 function in vivo.
RESULTS: Firstly, we found that HERC4 was significantly downregulated in ovarian cancer. We then found that ovarian cancer patients with high HERC4 expression had significantly higher overall survival and progression-free survival rates compared with patients with low expression. Then, HERC4 was overexpressed in ovarian cancer cells, and we found that overexpression of HERC4 significantly inhibited ovarian cancer cell growth, as well as the expression of the target protein SMO, and the key proteins in the downstream hedgehog signaling pathway. Finally, the xenograft tumor models revealed that overexpression of HERC4 significantly inhibited tumor growth in vivo.
CONCLUSIONS: Overall, these results indicate that overexpression of HERC4 inhibits cell proliferation of ovarian cancer in vitro and in vivo, suggesting that HERC4 may serve as an effective target for the treatment of ovarian cancer.

Congenital tibial hemimelia (CTH [MIM: 275220]) is a rare congenital limb deficiency that manifests as a shortened, curved, dysplastic or absent tibia with polydactyly. In previous studies, mutations of a distant sonic hedgehog (SHH) cis-regulator (ZRS) and a Shh repressor (GLI3) were identified.
Here, we admitted a 20-month-old boy who manifested with right tibial deformity, varus foot, ankle dislocation, and ipsilateral preaxial polydactyly. After genetic sequencing and data analysis, the results revealed a 443 A > G mutation in the father and a 536 C > T mutation in the mother in exon 2 of the Smoothed (SMO) gene at 7q32.1, with the coexistence of both mutant alleles in the proband/patient.
Our report suggests that even though not previously reported, SMO mutations may be associated with limb anomalies such as tibial hemimelia via Hh signaling in humans and has implications for genetic counseling.