Advanced Metastasis Research Articles

BUD23 promote the cell proliferation ability by affecting the PPAR signaling pathways: evidence from the online dataset and cell experiment

IntroductionProstate cancer is a major public health challenge for men worldwide, being the second most common cancer diagnosis and the fifth leading cause of cancer-related deaths among men. The etiology of prostate cancer is multifactorial, with age, genetic predispositions, and lifestyle factors playing critical roles. The role of the peroxisome proliferator-activated receptors (PPARs) in prostate cancer remains complex and not fully elucidated.MethodsTranscriptomic data from The Cancer Genome Atlas (TCGA) were utilized for this study. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). A prognosis-prediction model was constructed using Cox regression and LASSO analysis. Functional experiments, including Western blotting, quantitative PCR (qPCR), Cell Counting Kit-8 (CCK-8) assays, and EdU incorporation assays, were performed to validate the role of BUD23 in prostate cancer.ResultsSignificant differences were observed in the immune microenvironment and HLA gene expression profiles between high and low PPAR expression groups in prostate cancer. The high PPAR group exhibited a less active immune microenvironment with higher fractions of immunosuppressive T regulatory cells (Tregs). A robust prognostic model identified key genes, including BUD23, associated with patient survival. Elevated BUD23 expression was correlated with more aggressive clinical features such as advanced pathological stages, nodal metastasis, and higher Gleason scores. Knockdown of BUD23 in PC-3 and LNCaP prostate cancer cell lines significantly inhibited cell proliferation. Western blotting and qPCR confirmed effective BUD23 knockdown, and CCK-8 and EdU assays demonstrated reduced cell proliferation. BUD23 knockdown resulted in significant reductions in PPAR-α, PPAR-β, and PPAR-γ protein levels, suggesting a regulatory axis between BUD23 and PPARs in prostate cancer.ConclusionThe study highlights the distinct roles of PPARα, PPARβ/δ, and PPARγ in prostate cancer progression and their potential as therapeutic targets. Elevated BUD23 expression is associated with aggressive prostate cancer features and patient survival, making it a potential prognostic biomarker. The knockdown of BUD23 not only inhibited cell proliferation but also reduced the expression of PPAR-related proteins, indicating a potential regulatory axis between BUD23 and PPARs. These findings suggest that targeting BUD23 could modulate PPAR signaling and inhibit tumor growth in prostate cancer.

Revealing key proteins in comparison of tumor and para-tumor tissues in stage I esophageal squamous cell carcinoma: A combined gene expression clustering and protein interaction network analysis

Esophageal Squamous Cell Carcinoma (ESCC) which is diagnosed in advanced stages and metastasis to the vital organs, remained the sixth fatal malignancy among other types of cancer-related death. Considering the lack of specific clinical symptoms in the early development of the disease, finding suitable biomarkers and tissue-specific alterations for effective screening of ESCC is targeted in this project. Gene expression profiles of tumor tissue and para-tumors of stage I ESCC patients were retrieved from the Gene Expression Omnibus (GEO) database. The significant tissue-specific differentially expressed genes (DEGs) were identified and studied based on fold change distribution and the functional role of genes in the action map. A total number of 11,483 significant DEGs discriminated the tumor tissue from para-tumor tissue. Clustering analysis of significant DEGs led to identifying 220 DEGs as the final significant genes. Protein interaction network and action map analysis of the final gene list showed matrix metallopeptidase-9 (MMP9) as the critical gene related to the development of ESCC diseases in stage I. Significant expression change of MMP9 in esophageal carcinoma was validated in UALCAN (The University of Alabama at Birmingham Cancer Data Analysis Portal). This study highlighted the pivotal role of MMP9 in combination with SPP1, MMP13, and IL18 as a possible biomarkers panel in studies of tumor invasion and prognosis for stage I ESCC disease.

Prognostic analysis of early-onset and late-onset nasopharyngeal carcinoma: a retrospective study

PurposeThere are few studies on early-onset and late-onset nasopharyngeal cancer (EONPC and LONPC, defined as cancers in those aged < 50 and ≥ 50 years, respectively). This study aimed to determine the clinical and survival characteristics of patients with NPC in these two age groups.MethodsThis study involved patients diagnosed with NPC between 2000 and 2018, as per the Surveillance, Epidemiology, and End Results (SEER) database, and in our institution from 2014 to 2017. The clinicopathological characteristics, treatment modalities, and survival outcomes of patients with EONPC and LONPC were analyzed and compared.ResultsA total of 2943 patients from the SEER database and 833 domestic patients from our center were enrolled in the study. The EONPC group showed a better prognosis than LONPC (p < 0.001), despite a worse staging of regional lymph node metastasis (p < 0.001). Similar results were validated at our center; further, patients with EONPC presented more EBV-DNA positive rates (58% vs. 36.8%, p < 0.001) than those with LONPC. Further, the EONPC group had a superior overall survival (OS) (p = 0.017) and cancer-specific survival (CSS) (p = 0.004) compared to that of the LONPC patients. Univariate and multivariate Cox regression analyses revealed EONPC to be independently associated with a higher five-year OS.ConclusionsThough the EONPC group presented with more advanced clinical stages and lymph node metastasis, they showed better survival than the LONPC group. Age ≤ 50 years was an independent prognostic factor for survival outcomes in patients with NPC. Further studies on EONPC are warranted to achieve a better individualized therapeutic regimen.

The Role of Urinary Extracellular Vesicles in Kidney Cancer: Diagnostic and Therapeutic Potential

Renal cancer ranks as the 14th most common cancer globally, with renal cell carcinoma (RCC) being the primary variant, arising from renal tubular epithelial cells; clear cell RCC constitutes about 80% of cases. Despite their limitations, surgery and targeted therapy remain the mainstays of RCC treatment. Regardless of advancements in RCC research, substantial obstacles continue to exist, such as delayed diagnosis, advanced distant metastasis, and drug resistance. As urine is an easily accessible biofluid, the identification of EVs has paved the way for novel biomarker research. Urinary extracellular vesicles (uEVs) are a novel source of biomarkers with potential applications in cancer detection and management, utilizing a less invasive approach. New data indicate that uEVs are crucial in several areas of RCC, containing tumor development, metastasis, immune evasion, and response to drugs. These vesicles facilitate intercellular communication by transporting a variety of bioactive substances, including RNA, DNA, proteins, and lipids, and are released into the extracellular space by the majority of cell types. uEVs RNAs and proteins are presently being investigated for their possible application as diagnostic biomarkers for different types of kidney cancer. This review summarizes the most recent research examining the potential of uEVs cargo as a biomarker for the diagnosis, prognosis, and treatment of renal cancer.

Poria cocos inhibits the invasion, migration, and epithelial–mesenchymal transition of gastric cancer cells by inducing ferroptosis in cells

ObjectiveGastric cancer (GC) is one of the most prevalent malignant tumors of the digestive system. The advanced metastasis of gastric cancer severely limits the conventional approaches for its treatment, while certain traditional Chinese medicinal compounds have been reported to possess promising abilities in inhibiting tumor metastasis. Such as Poria (PA), known as Fu Ling in Chinese, is a commonly used traditional Chinese medicinal herb derived from Poria cocos, a fungus belonging to the polyporaceae family.MethodsThe proliferation capacity of cells was measured using the MTT assay, while the invasion and migration abilities of cells after treatment with different concentrations of PA were evaluated through wound healing assay and Transwell assay. The differential expression of mRNA was analyzed using qPCR. The in vivo growth of tumors was assessed by subcutaneous tumor formation in mice.ResultsBoth in vivo and in vitro experiments have demonstrated that PA significantly inhibits the proliferation of GC. Moreover, in vitro experiments have revealed that PA not only suppresses the invasion and migration of GC cells but also reverses TNF-β-induced EMT. Further experiments have revealed that PA inhibits cell invasion, migration and EMT by inducing ferroptosis in GC cells.ConclusionIn brief, the present study shows that PA inhibits tumor metastasis by inducing ferroptosis in GC cells. Our findings suggest that PA may have therapeutic potential in GC.

LEF1 is associated with immunosuppressive microenvironment of patients with lung adenocarcinoma.

Wnt/β-Catenin pathway plays an important role in the occurrence and progression of malignant tumors, especially PD-L1-mediated tumor immune evasion. However, the role of TCF/LEF, an important member of the Wnt/β-catenin pathway, in the tumor immunosuppressive microenvironment of lung adenocarcinoma (LUAD) remains unknown. LUAD tissue-coding RNA expression data from The Cancer Genome Atlas and TIMER databases were used to analyze the expression of TCF/LEF transcription factors and their correlation with various immune cell infiltration. Immunohistochemistry and immunofluorescence were used to detect tissue protein staining in 105 patients with LUAD. LEF1, TCF7, TCF7L1 and TCF7L2 were all aberrantly expressed in the tumor tissues of LUAD patients with the data from The Cancer Genome Atlas (TCGA) database, tumor immune estimation resource (TIMER) database and results of immunohistochemistry, but only LEF1 expression was associated with 5-year overall survival in LUAD patients. LEF1 protein expression was associated with advanced tumor node metastasis (TNM) stage, lymphatic metastasis and local invasion in 105 cases LUAD patients. At the same time, LEF1 mRNA expression was also associated with immunosuppressive microenvironment in LUAD patients with the data from TCGA database and TIMER database. Results of immunohistochemistry and immunofluorescence in tumor tissues of 105 cases LUAD patients showed that there was a positively correlation between LEF1 protein expression and the infiltration of M2 macrophages and Treg cells. LEF1 was highly expressed in tumor tissues of LUAD patients, and highly expressed LEF1 was associated with the immunosuppressive microenvironment of LUAD patients.

6504 Cerebellar Metastases from Papillary Thyroid Cancer; An Unusual Presentation

Abstract Disclosure: L.E. Chozet: None. A. Gilbert: None. M.A. Escobar Vasco: None. Background: Differentiated papillary thyroid cancer is known to have a very favorable prognosis. Brain metastases arising from papillary thyroid carcinoma are a very rare complication seen in approximately 1% of all cases of differentiated thyroid cancer with cerebellar metastases being even more uncommon. We present a case of a patient presenting with ataxia as the initial and only symptom of papillary thyroid carcinoma, found to have cerebellar metastases. Clinical Case: A 68-year-old man presented with ataxia for 1 week prior to arrival to hospital. CT head revealed hyperdense lesions in the right frontal lobe and left posterior cerebellar hemisphere. The patient underwent resection of left cerebellar mass with final pathology consistent with metastatic papillary thyroid carcinoma. Tumor cells were positive for TTF-1, thyroglobulin, CAM5.2, CK7, and PAX8, and negative for CK5/6, CK20, inhibin, and Napsin A. Ultrasound of the thyroid revealed multinodular goiter with dominant left thyroid lobe nodule 4 cm in size. PET CT showed left Thyroid mass with direct extension to adjacent lymph nodes, right anterior rib mass, left adrenal metastasis and right frontal lobe and left cerebellar metastasis. He received stereotactic radiosurgery with 5 out of 5 treatments completed. He subsequently underwent total thyroidectomy with left modified radical neck dissection, with pathology showing pT3bN1bM1. Next Generation Sequence positive for V600E, RADS1CR193, TERT PROMOTER -124C&amp;gt;T. After multidisciplinary team discussion, it was determined that the best course of action was to refer the patient to MD Anderson for evaluation, candidacy for prospective therapeutic clinical trials. Conclusion: This case demonstrates how differentiated papillary thyroid cancer, despite its favorable prognosis, can still prove to be a dangerous disease especially if undiagnosed for several years. This case also illustrates how papillary thyroid carcinoma can remain clinically silent for years and first present with atypical symptoms consistent with advanced metastases. Presentation: 6/2/2024

The prognostic impact of tumor deposits in colorectal cancer: More than just N1c.

The identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) aside from N1c lymph node designation. The objective of this study was to determine the prognostic impact, beyond American Joint Committee on Cancer N1c designation, of TDs among patients with primary CRC. Patients who had resected stage I-III primary CRC diagnosed between 2010 and 2019 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer-specific survival (CSS) stratified by TD status and lymph node (N) status was calculated using the Kaplan-Meier method and multivariable Cox proportional hazards regression analyses. In total, 147,783 patients with primary CRC were identified. TDs were present in 15,444 patients (10.5%). The presence of TDs was significantly associated with adverse tumor characteristics, including advanced pathologic stage, nodal status, and metastasis status. The presence of TDs was associated with worse CSS (hazard ratio [HR], 3.12; 95% confidence interval [CI], 3.02-3.22), as it was for each given N category (e.g., N2a and TD-negative [HR, 2.50; 95% CI, 2.37-2.64] vs. N2a and TD-positive [HR, 3.75; 95% CI, 3.49-4.03]). The presence of multiple TDs was also associated with decreased CSS for each given N category compared with a single TD (e.g. N2a with one TD [HR, 3.09; 95% CI, 2.65-3.61] vs. N2a with two or more TDs [HR, 4.32; 95% CI, 3.87-4.82]). TDs were identified as an independent predictor of a worse outcome in patients with CRC. The presence of TDs confers distinctly different CSS and provides important prognostic information among patients with CRC and warrants further investigation as a unique variable in future iterations of CRC staging.

The Immunosuppressive Receptor CD32b Regulation of Macrophage Polarization and Its Implications in Tumor Progression.

Macrophages, pivotal components of the immune system, orchestrate host defense mechanisms in humans and mammals. Their polarization into classically activated macrophages (CAMs or M1) and alternatively activated macrophages (AAMs or M2) dictates distinct functional roles in immunity and tissue homeostasis. While the negative regulatory role of CD32b within the FC gamma receptor (FCγR) family is recognized across various immune cell types, its influence on macrophage polarization remains elusive. This study aimed to elucidate the regulatory role of CD32b in macrophage polarization and discern the differential expression markers between the M1 and M2 phenotypes following CD32b siRNA transfection. The results revealed a decrease in the CD32b levels in lipopolysaccharide (LPS)-treated M1 and an increase in interleukin-4 (IL-4)-treated M2 macrophages, as observed in macrophage Raw264.7 cells. Furthermore, CD32b siRNA transfection significantly downregulated the M2 markers (IL-10, VEGF, Arg-1, and STAT6), while upregulating the M1 markers (IL-6, NF-κB, NOS2, and STAT1) in the Raw264.7 cells. Similar findings were recapitulated in macrophage-rich adherent cells isolated from mouse spleens. Additionally, the cytopathological analysis of pleural effusions and ascitic fluids from patients with cancer revealed a positive correlation between advanced tumor stages, metastasis, and elevated CD32b levels. In conclusion, this study highlights the regulatory influence of CD32b in suppressing M1 expression and promoting M2 polarization. Moreover, heightened M2 activation and CD32b levels appear to correlate with tumor progression. A targeted CD32b blockade may serve as a novel therapeutic strategy to inhibit M2 macrophage polarization and is promising for anti-tumor intervention.

577. OUTCOMES OF SIMULTANEOUS RESECTION AND RECONSTRUCTION OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA SYNCHRONOUSLY ASSOCIATED WITH HEAD AND NECK CANCER

Abstract In 1953, a study by Slaughter et al. on oral cancer proposed that field cancerization is the phenomenon of widespread carcinogenesis across multiple regions due to long-term exposure to common cancer-causing factors. Esophageal squamous cell carcinoma (ESCC) and head and neck cancer (HNC) share common risks, such as smoking and alcohol consumption, and are often observed synchronously. Therefore, treatment strategies based on tumor stages are important. In our hospital, for synchronous HNC and thoracic ESCC, local resection is indicated if the HNC is ≤T2, and resection with reconstruction is indicated if the HNC is ≥T3, and a one-stage operation for thoracic ESCC and HNC was generally performed. Here, we examined treatment strategies based on the results of simultaneous resection and reconstruction of synchronous thoracic ESCC and HNC in our hospital. A total of 174 patients with esophageal cancer underwent surgery at our hospital between January 2008 and December 2023. Among them, 16 (9%) had 18 lesions of synchronous HNC and nine patients (5%) underwent simultaneous resection and reconstruction. Patients with thoracic ESCC had Ut/Mt/Lt; 1/6/2; T-factor, T1/2/3; 5/2/2; N-factor, N0/1:6/3; and clinical stage, stage I/II; 2/6. For synchronous HNC, hypopharyngeal/oropharyngeal/laryngeal/cervical esophageal cancer; 5/2/1/2; T factor was T2/3/4; 1/6/3; N factor was N0/1/2c/3a/3b; 4/2/2/2/1/1; and clinical stage was stage II/III/IV; 1/5/4. Six patients underwent surgery after preoperative chemotherapy or chemoradiotherapy. Total pharyngo-laryngo-esophagectomy (TPLE) was performed using a thoracoscopic transthoracic approach in six patients, transhiatal approach in two, and mediastinoscopic approach in one. Regarding reconstruction, a gastric tube was used in nine patients, including eight patients in whom it was interposed with the free jejunal autograft. The median operative time was 929 min (590–1248 min) and median blood loss was 622 mL (213–1764 mL). Only patients with skin valve necrosis underwent reoperation; however, there were no hospital deaths, and the median postoperative hospital stay was 39 days (28–59 days). Recurrence was observed in four cases. All cases were considered to be due to HNC, and three were stage IV cases with advanced lymph node metastasis. Simultaneous resection and reconstruction for synchronous HNC and the thoracic esophagus is a highly invasive treatment that can be performed safely. Recurrence has been observed in advanced cases of HNC, and further development of multidisciplinary treatment, including preoperative chemotherapy, is necessary.

Role of osteoclast inhibitors in prostate cancer bone metastasis; a narrative review.

To study the role of Osteoclast inhibitors in advanced prostate cancer metastasis treatment and their efficacy in reducing skeletal related events. A comprehensive search was done using search terms as "osteoclast inhibitors" "Bisphosphonates" "Zoledronic acid" " pamidronate" " Alendronate" "Denosumab" " Prostate cancer metastasis" in pubmed and Google scholar. Relevant articles were screened and collected . The collected articles were used to frame the review and data showing use of Osteoclast inhibitors In prostate cancer bone metastasis was collected. Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life.Initially, radiation therapy and radiopharmaceuticals were the mainstay of treatment however the role of Bisphosphonates and denosumab has become an integral part of therapy to manage metastatic prostate cancer. These agents significantly decrease skeletal related events and enhance patients quality of life. Emerging therapies like Radium-223 have also shown promise in reducing skeletal related events and also improving survival rates in patients with bone metastasis. Other treatment options which are being used are systemic agents like Docetaxel, cabazitaxel, hormonal therapies like abiraterone and enzalutamide. Immunotherapy with sipuleucel-T has demonstrated a reduction in mortality among prostate cancer patients with metastasis, highlighting the need for further research in this area. Ongoing studies are investigating novel agents that target both tumor cells and the bone microenvironment. Osteoclast inhibitors are effective in reducing skeletal related events in advanced bone metastasis and improve the quality of life of patients.

Matching-Adjusted Indirect Comparison of the Efficacy and Safety of Erdafitinib vs Enfortumab Vedotin in Patients with Locally Advanced Metastatic Urothelial Carcinoma.

Background: For patients with locally advanced or metastatic urothelial carcinoma (la/mUC), prognosis is poor and effective treatment options are limited. Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA for the treatment of adults with la/mUC harboring FGFR alterations whose disease progressed following at least 1 prior line of therapy, including a PD-1 or PD-L(1) inhibitor, based on the phase 3, randomized THOR trial (NCT03390504, Cohort 1). Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an anchored matching-adjusted indirect comparison (MAIC). Methods: An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. Individual patient data from THOR were adjusted to match published key eligibility criteria and average baseline characteristics of EV-301, such as Bellmunt risk score, liver or visceral metastases, primary site, among others. Erdafitinib was then indirectly compared with EV using the relative treatment effects for the reweighted THOR population and those published for EV-301. Results: After matching, the effective sample size for THOR was 126 patients. The MAIC-recalculated hazard ratio (95% credible interval) for erdafitinib vs EV was 0.92 (0.54, 1.57) for overall survival and 0.93 (0.55, 1.56) for progression-free survival, yielding Bayesian probabilities of erdafitinib being better than EV of 62.1% and 60.5%, respectively. For response outcomes, the MAIC-recalculated risk ratio was 1.49 (0.56, 3.90) for confirmed objective response rate and 2.89 (0.27, 30.33) for confirmed complete response with probabilities of 72.6% and 81.3% for erdafitinib being better than EV, respectively. For safety, MAIC-yielded risk ratios of 1.09 (0.99, 1.21) for any treatment-related adverse events, 0.86 (0.57, 1.28) for grade 3+ TRAEs, and 1.02 (0.98, 1.06) for any treatment-emergent adverse events. Conclusion: The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

Matching-Adjusted Indirect Comparison of the Efficacy and Safety of Erdafitinib vs Enfortumab Vedotin in Patients with Locally Advanced Metastatic Urothelial Carcinoma

Background: For patients with locally advanced or metastatic urothelial carcinoma (la/mUC), prognosis is poor and effective treatment options are limited. Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA for the treatment of adults with la/mUC harboring FGFR alterations whose disease progressed following at least 1 prior line of therapy, including a PD-1 or PD-L(1) inhibitor, based on the phase 3, randomized THOR trial (NCT03390504, Cohort 1). Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an anchored matching-adjusted indirect comparison (MAIC). Methods: An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician’s choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. Individual patient data from THOR were adjusted to match published key eligibility criteria and average baseline characteristics of EV-301, such as Bellmunt risk score, liver or visceral metastases, primary site, among others. Erdafitinib was then indirectly compared with EV using the relative treatment effects for the reweighted THOR population and those published for EV-301. Results: After matching, the effective sample size for THOR was 126 patients. The MAIC-recalculated hazard ratio (95% credible interval) for erdafitinib vs EV was 0.92 (0.54, 1.57) for overall survival and 0.93 (0.55, 1.56) for progression-free survival, yielding Bayesian probabilities of erdafitinib being better than EV of 62.1% and 60.5%, respectively. For response outcomes, the MAIC-recalculated risk ratio was 1.49 (0.56, 3.90) for confirmed objective response rate and 2.89 (0.27, 30.33) for confirmed complete response with probabilities of 72.6% and 81.3% for erdafitinib being better than EV, respectively. For safety, MAIC-yielded risk ratios of 1.09 (0.99, 1.21) for any treatment-related adverse events, 0.86 (0.57, 1.28) for grade 3+ TRAEs, and 1.02 (0.98, 1.06) for any treatment-emergent adverse events. Conclusion: The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

WNT5B promotes the malignant phenotype of non-small cell lung cancer via the FZD3–DVL3–RAC1–PCP–JNK pathway

The WNT5B ligand regulates the non-canonical wingless-related integration site (WNT)–planar cell polarity (PCP) pathway. However, the detailed mechanism underlying the activity of WNT5B in the WNT–PCP pathway in non-small cell lung cancer (NSCLC) is unclear. In this study, we assessed the clinicopathological significance of WNT5B expression in NSCLC specimens. WNT5B-overexpression and -knockdown NSCLC cell lines were generated in vivo and in vitro, respectively. WNT5B overexpression in NSCLC specimens correlates with advanced tumor node metastasis (TNM) stage, lymph node metastasis, and poor prognosis in patients with NSCLC. Additionally, WNT5B promotes the malignant phenotype of NSCLC cells in vivo and in vitro. Interactions were identified among WNT5B, frizzled3 (FZD3), and disheveled3 (DVL3) in NSCLC cells, leading to the activation of WNT–PCP signaling. The FZD3 receptor initiates DVL3 recruitment to the membrane for phosphorylation in a WNT5B ligand-dependent manner and activates c-Jun N-terminal kinase (JNK) signaling via the small GTPase RAC1. Furthermore, the deletion of the DEP domain of DVL3 abrogated these effects. Overall, we demonstrated a novel signal transduction pathway in which WNT5B recruits DVL3 to the membrane via its DEP domain through interaction with FZD3 to promote RAC1–PCP–JNK signaling, providing a potential target for clinical intervention in NSCLC treatment.

Long noncoding RNA LINC01550 inhibits colorectal cancer malignancy by suppressing the Wnt/β-catenin signaling pathway.

Colorectal cancer (CRC) is a common gastrointestinal malignancy. Long noncoding RNAs (lncRNAs) are associated with the progression of various cancers, including CRC. Herein, we explored the function of lncRNA LINC01550 in CRC. LINC01550 expression in CRC was analyzed using The Cancer Genome Atlas (TCGA). The diagnostic value of LINC01550 was evaluated using ROC curves. The relationship between clinicopathological variables and LINC01550 expression was explored, and its prognostic value was assessed using Kaplan-Meier and Cox regression analyses. The relationship between LINC01550 expression and immune cell infiltration was analyzed using CIBERSORT. Tumor-associated mutations and drug sensitivity were compared between high and low LINC01550 expression groups. The effects of LINC01550 overexpression on CRC cells were investigated using CCK-8, flow cytometry, wound healing, Transwell, qRT-PCR, and western blot assays. LINC01550 was downregulated in CRC tissues, and the low expression of LINC01550 was correlated with advanced stage and metastasis. CRC patients with low LINC01550 expression had poorer overall survival. LINC01550 expression was an independent risk factor for CRC prognosis. APC and TP53 mutations were more frequent in the low LINC01550 expression group, while the high LINC01550 expression group was significantly more sensitive to 5-fluorouracil, irinotecan, trametinib, gemcitabine, rapamycin, and XAV939. LINC01550 overexpression suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition of HCT-116 and HT-29 cells and promoted apoptosis. LINC01550 exerted these effects by inhibiting Wnt/β-catenin signaling. Our results suggest LINC01550 as a diagnostic and prognostic predictor in CRC that acts as a tumor suppressor and a potential therapeutic target.

LINC00518: a key player in tumor progression and clinical outcomes.

Long non-coding RNAs (lncRNAs), defined as RNA molecules exceeding 200 nucleotides in length, have been implicated in the regulation of various biological processes and the progression of tumors. Among them, LINC00518, a recently identified lncRNA encoded by a gene located on chromosome 6p24.3, consists of three exons and is predicted to positively regulate the expression of specific genes. LINC00518 has emerged as a key oncogenic lncRNA in multiple cancer types. It exerts its tumor-promoting effects by modulating the expression of several target genes, primarily through acting as a sponge for microRNAs (miRNAs). Additionally, LINC00518 influences critical signaling pathways, including the Wnt/β-catenin, JAK/STAT, and integrin β3/FAK pathways. Elevated levels of LINC00518 in tumor tissues are associated with increased tumor size, advanced clinical stage, metastasis, and poor survival prognosis. This review provides a comprehensive summary of the genetic characteristics, expression patterns, biological functions, and underlying mechanisms of LINC00518 in human diseases.

Natural products and long noncoding RNA signatures in gallbladder cancer: a review focuses on pathogenesis, diagnosis, and drug resistance.

Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs) and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. Curcumin, baicalein, oleanolic acid, shikonin, oxymatrine, arctigenin, liensinine, fangchinoline, and dioscin are a few examples of natural compounds that have demonstrated promising anticancer activities against GBC through the regulation of important signaling pathways. The lncRNAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC, are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR activate oncogenes such as DNMT1, Wnt/β-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor proteins NF-κB, EZH2, and miR-421. Clinically, specific lncRNAs can serve as diagnostic or prognostic biomarkers based on overexpression correlating with advanced TNM stage, metastasis, chemoresistance, and poor survival. Therapeutically, targeting aberrant lncRNAs with siRNA or antisense oligos disrupts their oncogenic signaling and inhibits GBC progression. Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.

Telomere-related gene risk model for prognosis prediction in colorectal cancer.

Colorectal cancer (CRC) is the third-most prevalent cancer globally. The biological significance of telomeres in CRC carcinogenesis and progression is underscored by accumulating data. Nevertheless, not much is known about how telomere-related genes (TRGs) affect CRC prognosis. Therefore, the aim of this study was to investigate the role of TRGs in CRC prognosis. We retrospectively obtained the expression profiles and clinical data of CRC patients from public databases. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, we created a telomere-related risk model to predict survival outcomes, identifying ten telomere-related differentially expressed genes (TRDEGs). Based on TRDEGs, we stratified patients from The Cancer Genome Atlas (TCGA) into low- and high-risk subsets. Subsequently, we conducted comprehensive analyses, including survival assessment, immune cell infiltration, drug sensitivity, and prediction of molecular interactions using Kaplan-Meier curves, ESTIMATE, CIBERSORT, OncoPredict, and other approaches. The model showed exceptional predictive accuracy for survival. Significant differences in survival were observed between the two groups of participants grouped according to the model (P<0.001), and this difference was further confirmed in the external validation set (GSE39582) (P=0.004). Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4+ T cells, effector memory CD4+ T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature's capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced. Overall, we constructed a telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.

Ovarian cancer: A review for primary care providers.

Ovarian cancer is the second most common gynecologic cancer in the United States and the deadliest gynecologic cancer worldwide, with a 5-year survival rate of less than 50%. Because of its vague symptoms, more than half of patients present with advanced disease and metastasis. This article reviews the epidemiology, pathogenesis, risk factors, screening, presentation, and diagnosis of ovarian cancer, in addition to providing an overview of the standard approach to treatment and novel targeted biologic therapies.

Significance of dysregulated M2 macrophage and ESR2 in the ovarian metastasis of gastric cancer.

Prognosis of gastric cancer (GC) patients with ovarian metastasis (OM) remains poor. We hereby characterized the role of tumor immune microenvironment (TIME) and identified potential key regulators in the OM with the aim of understanding its molecular basis to develop novel therapeutic targets. Transcriptomic analyses of paired primary and ovarian metastatic lesions of seven GC patients from Fudan University Shanghai Cancer Center uncovered and functionally annotated their differentially expressed genes (DEGs). CIBERSORT analysis revealed differential TIME between primary GCs and OMs, which was further validated by multiplex immunofluorescence (mIF). Unique overexpression of candidate regulator in OMs was validated by an immunohistochemical (IHC) staining-based cohort study and in vitro cell growth, migration and invasion assays were conducted to characterize its function in GC progression. Functional enrichment analyses of DEGs between GCs and matched OMs revealed multiple significantly dysregulated immune-related and cancer-related pathways. Distinctive subsets of immune cells, especially M2 macrophage, were selectively enriched in metastatic lesions. mIF-based quantification further validated the overexpression of CD68+CD206+ M2 macrophage in the OMs. Estrogen receptor 2 (ESR2), which encodes estrogen receptor β (ERβ), was not only potentially correlated with M2 macrophage but also overexpressed in the OM of GC. ESR2 was up-regulated in cancerous tissue and its high expression correlated with younger age, more advanced lymph node metastasis and pathological stage, as well as a worse patient survival. IHC staining of ERβ in the cohort of paired primary and metastatic GCs validated its selective overexpression in OMs. Small-interfering RNAs (siRNAs)-induced knockdown of ESR2 significantly inhibited the invasion and migration of both AGS and HGC-27 GC cell lines. Comparative RNA-sequencing analysis revealed the dysregulated TIME, M2 macrophage in particular, between primary GC and OM. ESR2 potentially correlated with M2 macrophage and played pro-oncogenic roles in GC progression and metastasis.