UCHL3 inhibits ferroptosis by stabilizing ß-catenin and maintains stem-like properties of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/ß-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of ß-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of ß-catenin in HCC cells. TOP-luciferase activity and ß-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of ß-catenin is required for the interaction with UCHL3. UCHL3 increases ß-catenin protein stability via removing K48-specific poly-ubiquitin chains from ß-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of ß-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of ß-catenin. In general, our results indicates that UCHL3 increases the stability of ß-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.

The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. Video Abstract.

Multi-omics analysis reveals a molecular landscape of the early recurrence and early metastasis in pan-cancer.

Cancer remains a formidable challenge in medicine due to its propensity for recurrence and metastasis, which can result in unfavorable treatment outcomes. This challenge is particularly acute for early-stage patients, who may experience recurrence and metastasis without timely detection. Here, we first analyzed the differences in clinical characteristics among the primary tumor, recurrent tumor, and metastatic tumor in different stages of cancer, which may be caused by the molecular level. Moreover, the importance of predicting early cancer recurrence and metastasis is emphasized by survival analyses. Next, we used a multi-omics approach to identify key molecular changes associated with early cancer recurrence and metastasis and discovered that early metastasis in cancer demonstrated a high degree of genomic and cellular heterogeneity. We performed statistical comparisons for each level of omics data including gene expression, mutation, copy number variation, immune cell infiltration, and cell status. Then, various analytical techniques, such as proportional hazard model and Fisher's exact test, were used to identify specific genes or immune characteristics associated with early cancer recurrence and metastasis. For example, we observed that the overexpression of BPIFB1 and high initial B-cell infiltration levels are linked to early cancer recurrence, while the overexpression or amplification of ANKRD22 and LIPM, mutation of IGHA1 and MUC16, high fibroblast infiltration level, M1 polarization of macrophages, cellular status of DNA repair are all linked to early cancer metastasis. These findings have led us to construct classifiers, and the average area under the curve (AUC) of these classifiers was greater than 0.75 in The Cancer Genome Atlas (TCGA) cancer patients, confirming that the features we identified could be biomarkers for predicting recurrence and metastasis of early cancer. Finally, we identified specific early sensitive targets for targeted therapy and immune checkpoint inhibitor therapy. Once the biomarkers we identified changed, treatment-sensitive targets can be treated accordingly. Our study has comprehensively characterized the multi-omics characteristics and identified a panel of biomarkers of early cancer recurrence and metastasis. Overall, it provides a valuable resource for cancer recurrence and metastasis research and improves our understanding of the underlying mechanisms driving early cancer recurrence and metastasis.

Association between preoperative denosumab and the risk of local recurrence in patients with giant cell tumor of bone: A meta-analysis and systematic review.

Objectives: This meta-analysis aimed at determining the association between preoperative denosumab and the risk of local recurrence in patients with giant cell tumors of the bone. Methods and Materials: Web of Science, EMBASE, Cochrane Library, and PubMed were comprehensively searched on April 20th, 2022. Data from the included articles were analyzed using meta-analysis. The bias of all included studies was evaluated according to ROBINS-I. Also, subgroup and sensitivity analyses were performed. Results: Eight studies with 1270 cases (195 in the denosumab group and 1075 in the control group) were eventually included. Patients receiving denosumab before curettage had a higher risk of local recurrence than those who underwent curettage alone (odds ratio: 2.29, 95% confidence intervals: 1.44-3.64, P = 0.0005). The denosumab group showed a significantly higher risk of local recurrence in most subgroup analyses, except for those with preoperative denosumab duration ≤six months/doses (P = 0.66) and sample size ranging from 100 to 180 (P = 0.69). Conclusion: Denosumab before curettage may increase the risk of local recurrence in patients with giant cell tumor of the bone. Preoperative denosumab should be used with caution after weighing an increased risk of local recurrence against the clinical benefits and a duration time of less than six months before surgery is recommended.

A Discussion on the Criteria for Surgical Decision-Making in Elderly Patients With Metastatic Spinal Cord Compression.

STUDY DESIGN: Retrospective study. OBJECTIVES: Although the role of surgery in the management of metastatic spinal cord compression (MSCC) has been well established, elderly patients may still be denied surgery because of higher risk of complications and shorter life expectancy. The purpose of this study was to determine whether elderly patients with MSCC could benefit from surgery and discuss the criteria for surgical decision-making in such patients. METHODS: Enrolled in this study were 55 consecutive patients aged 75 years or older who were surgically treated for MSCC in our center. Prognostic factors predicting overall survival (OS) were explored by the Kaplan-Meier method and Cox regression model. The quality of life (QoL) of the patients was evaluated by the SOSGOQ and compared using Student's t test. Risk factors for postoperative complications were identified by Chi-square test and multiple logistic regression analysis. RESULTS: Surgical treatment for MSCC substantially improved the neurological function in 55.8% patients and QoL in 88.5% patients with acceptable rates of postoperative complications (16.4%), reoperation (9.1%), and 30-day mortality (1.8%). Postoperative ECOG-PS of 1-2, total en-bloc spondylectomy (TES), and postoperative chemotherapy were favorable prognostic factors for OS, while a high Charlson Comorbidity Index (CCI) and a long operation time were risk factors for postoperative complications. CONCLUSIONS: Surgery should be encouraged for elderly patients with MSCC 1) who are compromised by the current or potential neurological dysfunction; 2) with radioresistant tumors; 3) with spinal instability; and 4) with no comorbidity, ECOG-PS of 0-2, and systemic treatment adherence. In addition, surgery should be performed by a skilled and experienced surgical team.

Oncogenic signaling pathway dysregulation landscape reveals the role of pathways at multiple omics levels in pan-cancer.

Dysregulation of signaling pathways plays an essential role in cancer. However, there is not a comprehensive understanding on how oncogenic signaling pathways affect the occurrence and development with a common molecular mechanism of pan-cancer. Here, we investigated the oncogenic signaling pathway dysregulation by using multi-omics data on patients from TCGA from a pan-cancer perspective to identify commonalities across different cancer types. First, the pathway dysregulation profile was constructed by integrating typical oncogenic signaling pathways and the gene expression of TCGA samples, and four molecular subtypes with significant phenotypic and clinical differences induced by different oncogenic signaling pathways were identified: TGF-ß+ subtype; cell cycle, MYC, and NF2- subtype; cell cycle and TP53+ subtype; and TGF-ß and TP53- subtype. Patients in the TGF-ß+ subtype have the best prognosis; meanwhile, the TGF-ß+ subtype is associated with hypomethylation. Moreover, there is a higher level of immune cell infiltration but a slightly worse survival prognosis in the cell cycle, MYC, and NF2- subtype patients due to the effect of T-cell dysfunction. Then, the prognosis and subtype classifiers constructed by differential genes on a multi-omics level show great performance, indicating that these genes can be considered as biomarkers with potential therapeutic and prognostic significance for cancers. In summary, our study identified four oncogenic signaling pathway-driven patterns presented as molecular subtypes and their related potential prognostic biomarkers by integrating multiple omics data. Our discovery provides a perspective for understanding the role of oncogenic signaling pathways in pan-cancer.

Deep learning using bulk RNA-seq data expands cell landscape identification in tumor microenvironment.

The tumor microenvironment (TME) profoundly influences tumor progression and affects immunotherapy responses and resistance. Understanding its heterogeneity is the key for developing immunotherapy. However, the available methods can only partially portray the TME heterogeneity with a small number of cell types. Here, we developed a deep learning-based frame with a design visible, DCNet, that embeds the relationships between cells and their marker genes in the neural network, and can infer the cell landscape with more than 400 cell types based on bulk RNA-seq data. DCNet accurately recapitulated the cell landscape of multiple single cell RNA-seq datasets, which showed better robustness and stability. Based on the cell landscape of TCGA patients, which was built with DCNet, the patients were divided into two groups with significant differences in survival time and distinct cell-type populations. DCNet provides a foundation for decoding TME heterogeneity. The source code of DCNet can be found on GitHub: https://github.com/xindd/DCNet.

Elevation of miR-302b prevents multiple myeloma cell growth and bone destruction by blocking DKK1 secretion.

BACKGROUND: Myeloma bone disease (MBD) is a severe complication of multiple myeloma (MM) mainly due to an imbalance between enhanced osteoclast activity and reduced osteoblast function. Previous studies have demonstrated that miRNAs play a vital role in the osteogenic differentiation of mesenchymal stromal cells (MSCs) in MM. However, the value of miR­302b in MBD remains to be further elucidated. The aim of this study is to explore the role of miR­302b in the regulation of MBD osteogenic differentiation and evaluate the potential of a new therapeutic strategy for the clinical treatment of MBD. METHOD: Our previous research demonstrated that MiR-302b belongs to the miR-302 cluster and is able to inhibit tumor growth and osteolysis in an orthotopic osteosarcoma xenograft tumor mouse model. In this study, we first transfected miR-302b mimics, miR-302b inhibitor, and miR-302b NC into MM1.S and RPMI8226 MM cells to detect the correlation between miR-302b expression in the pathological specimens and the clinicopathological features by qPCR, the target correlation between miR-302b and DKK1 by immunohistochemistry, qPCR and Western blot, and the correlation between miR-302b and the Wnt/ß-catenin signaling pathway by Western blot. The effect of miR-302b on osteoblastogenesis was also studied in a subperiosteal tumorigenesis model of NOD/SCID nude mice. RESULTS: We found that increased miR-302b suppressed cell proliferation and induced cell apoptosis in RPMI 8226 and MM1.S cells. TargetScan online bioinformatic analysis predicted that miR-302b is able to bind to 3'UTR of DKK1 mRNA. Target binding of miR-302b to DKK1 was demonstrated by dual-luciferase reporter assay, qPCR, Western blot and immunohistochemistry, indicating that miR-302b is able to degrade DKK1 in RPMI 8226 and MM1.S cells. The model of co-culturing MM cells with preosteoblast MC3T3-E1 cells showed that miR-302b inhibits MM-induced suppression of osteoblast differentiation. Western blotting showed that miR-302b promotes the Wnt/ß-catenin signaling pathway in MM cells. Micro-CT and immunohistochemistry results showed that miR-302b suppresses myeloma bone destruction in vivo. CONCLUSION: miR-302b is able to target DKK1 and promote the Wnt/ß-catenin signaling pathway in MM.

Whole Genome Sequencing Identifies Key Genes in Spinal Schwannoma.

Spinal schwannoma is the most common primary spinal tumor but its genomic landscape and underlying mechanism driving its initiation remain elusive. The aim of the present study was to gain further insights into the molecular mechanisms of this kind of tumor through whole genome sequencing of nine spinal schwannomas and paired blood samples. The results showed that ATM, CHD4, FAT1, KMT2D, MED12, NF2, and SUFU were the most frequently mutated cancer-related genes. In addition, the somatic copy number alterations (CNA) was potentially associated with spinal schwannoma, among which NF2 was found to be frequently deleted in schwannoma samples. Only a few genes were located within the amplified regions. In contrast, the deleted regions in 15q15.1 and 7q36.1 contained most of these genes. With respect to tumorigenesis, NF2 had the highest variant allele frequency (VAF) than other genes, and homozygous deletion was observed in NF1, NF2, and CDKN2C. Pathway-level analysis suggested that Hippo signaling pathway may be a critical pathway controlling the initiation of spinal schwannoma. Collectively, this systematic analysis of DNA sequencing data revealed that some key genes including NF1, NF2, and CDKN2C and Hippo signaling pathway were associated with spinal schwannoma, which may help improve our understanding about the genomic landscape of spinal schwannoma.

Role of Multimodal Treatment in Urothelial Carcinoma Spinal Metastasis: 15 Patients' Experiences in a Single Center.

PURPOSE: Spinal metastasis from urothelial carcinoma (UC) is relatively uncommon. The aim of the present study is to explore the clinicopathological features, surgical treatments and outcomes of this rare disease. PATIENTS AND METHODS: Fifteen patients with UC spinal metastasis who received surgery in our center between 2009 and 2018 were retrospectively investigated. Clinical data, treatment options, and outcomes were analyzed. RESULTS: For the 15 patients (9 men and 6 women), the primary tumors were located in the upper urothelial tract in ten and lower urothelial tract in five. UC mainly metastasized to the lumbar spine in seven cases, followed by the thoracic spine in five. Pathologic fracture and soft tissue mass with dura mater compression were observed in 66.7% and 93.3% cases, respectively. Palliative resection was performed in nine cases and excisional resection in six. Eleven patients received postoperative chemotherapy, including three with a preoperative ECOG score >2. Bisphosphonates were administered in all patients. Pain was relieved remarkably in all patients, and both the neurological function and general status were improved significantly after surgery. The median overall survival was 14 months. Log rank test showed that patients receiving postoperative chemotherapy survived longer than those without chemotherapy (p=0.037). WHO grade 3 was also correlated with poorer prognosis (p=0.012). CONCLUSION: Pathological fracture and soft tissue mass with dura mater compression is frequently observed on radiological images in patients with UC spinal metastasis. Surgery is useful to prevent deterioration of performance status and improve quality of life, which provide an opportunity for further systematic therapy. Multimodal treatments, including surgery, postoperative chemotherapy and bisphosphonates are recommended. WHO grade 2 and receiving postoperative chemotherapy were favorable prognostic factors for the overall survival of patients with UC spinal metastasis.

Surgical Treatment of Spinal Cord Compression Caused by Metastatic Small Cell Lung Cancer: Ten Years of Experience in a Single Center.

PURPOSE: Metastatic spinal cord compression (SCC) secondary to small cell lung cancer (SCLC) is a disastrous oncological emergency, but it is poorly understood due to the small numbers of patients and their short survival times. Whether patients suffered from SCC caused by metastatic SCLC benefit from spinal surgery remains unknown. The aim of this study was to evaluate the role of surgical treatment and prognostic factors in patients with SCC caused by metastatic SCLC. METHODS: From 2009 to 2019, 30 consecutive patients surgically treated for metastatic SCC from SCLC were enrolled in this retrospective analysis. Kaplan-Meier method and Cox regression analysis were used to estimate overall survival (OS) and identify prognostic factors. Quality of life (QoL) was assessed by the three-level EuroQol-five-Dimensions (EQ-5D-3L) instrument and compared using Student's t test. RESULTS: The median OS time was 9 months in our series. Relief of pain, preservation of neurological function, and improvement of performance status were achieved after surgical intervention. The mean EQ-5D-3L utility score showed a significant improvement after surgery (0.3394 preoperatively vs 0.5884 postoperatively). According to Cox regression analysis, postoperative ECOG-PS and immunotherapy were identified to be independent prognostic factors for patients with SCC caused by metastatic SCLC. CONCLUSION: Despite the short life expectancy, prompt surgical decompression is extremely necessary for patients with SCC caused by SCLC, for surgery played a critical role in improving patients' QoL. Better performance status after surgery and receiving immunotherapy were associated with a longer OS.

Treatment strategies and outcomes for spinal rhabdomyosarcoma: A series of 11 cases in a single center and review of the literature.

OBJECTIVES: Rhabdomyosarcoma (RMS) involving the spine is rare. The aim of the present study is to explore the clinicopathological features, surgical treatments and outcomes of this rare disease. PATIENTS AND METHODS: Eleven patients with spinal RMS who received surgery in our institution between 2012 and 2018 were retrospectively investigated. The literature on spinal RMS was also reviewed. RESULTS: Our study consisted of 7 cases of primary RMS and 4 cases of metastatic RMS. Seven primary and one metastatic spinal RMS received radical resection, the remaining three metastatic patients received palliative resection. Eight patients died with a median survival time of 8 months. The mean value of Ki-67 positivity was 48.2 %. Literature review revealed a total of 22 previously reported cases. 54.5 % of the pooled cases of the 33 patients were under the age of 18. Of the 20 patients with primary spinal RMS, 9 cases were diagnosed as embryonal, while 6 of the 13 metastatic patients were diagnosed as alveolar. Multiple modalities, including surgery and concurrent adjuvant therapy were performed in 19 patients. The median overall survival (OS) for 28 patients with detailed follow-up information was 10 months. Radical resection offered a significant longer median OS than non-radical resection (18 vs. 6 months, p = 0.027). CONCLUSION: Spinal RMS mainly affects young patients. The embryonal form and alveolar form is the most frequent subtype for primary and metastatic spinal RMS respectively. Spinal RMS is highly aggressive with dismal prognosis. Multimodality therapies are the mainstay of treatment. Radical resection is strongly recommended in eligible patients.

Secondary aneurysmal bone cyst of the spine: Clinicopathological features, surgical modalities and outcomes.

OBJECTIVES: Spinal secondary aneurysmal bone cyst (SABC) is extremely rare with few published reports available at present. Our aim is to explore the clinicopathologic features, surgical modalities and outcomes of spinal SABC. PATIENTS AND METHODS: A retrospective study of 33 patients with spinal SABC who were surgically treated in our center between 2010 and 2018 was performed. Clinical data, treatment options, complications and outcomes were analyzed. RESULTS: Of the 33 patients, 12 were male and 21 were female, with a mean age of 32 years. Eleven lesions were located at the lumbar spine. The underlying lesions included giant cell tumor (GCT) (n = 20), osteoblastoma (n = 7), hemangiaoma (n = 3), fibrous dysplasia (n = 2) and osteosarcoma (n = 1). Preoperative selective arterial embolization was applied in 24 patients. All the patients were treated surgically through either subtotal resection (n = 1), piecemeal total resection (n = 21), or total en bloc resection (n = 11). Four patients experienced recurrence and one patient died during the follow-up period. CONCLUSION: Spinal SABC is popular in the third and fourth decade of life with female predominance. GCT is the most common underlying lesion. Preoperative arterial embolization is recommended, while surgery is the mainstay of treatment for spinal SABC. En bloc resection is recommended for spinal SABCs especially when underlying tumor is aggressive or malignant.

Diagnosis and microsurgical treatment of cavernous sinus hemangioma.

To investigate the diagnosis and microsurgical treatment of cavernous sinus hemangioma, the clinical data, including pathology, epidemiology, medical imaging, operation procedure, and post-operational complication of 12 cavernous sinus hemangioma patients undergoing operations in Affiliated Hospital of Medical College of Qingdao University from 1999 to 2008, were analyzed. There were 2 males and 10 females. The patients were aged from 28 to 61 years. Headaches and deficits of the cranial nerves coursing through the cavernous sinus were the principal symptoms at presentation. The common clinical manifestations were visual loss, diplopia, facial numbness, and extraocular muscle palsy. The radiological features in all patients were similar with a characteristic pattern of extension and encasement of carotid artery. CT showed the lesion as hypodense to isodense with marked enhancement after contrast administration. T1-weighted MR imaging showed the lesions as hypointense with marked enhancement after contrast administration. T2-weighted MR imaging showed the lesions as hyperintense. The maximum size of the lesion was 9 to 57 mm (mean 45 mm). Basal pterional craniotomies were used for eight patients. Orbitozygomatic osteotomies were used for two patients. Pterional approach was used for two patients. The lesions were removed through incising the lateral wall of the cavernous sinus. The tumor was totally removed in five cases, subtotally removed in four cases, and partially removed in two cases. The main post-operational complications included oculomotor nerve paralysis (four cases) and trigeminal nerve lesions (three cases). No postoperative death occurred. Operation is the best choice for cavernous sinous hemangioma. It was helpful to control bleeding through intradura and incising the lateral wall of the cavernous sinus.