EEF1A2 promotes HIF1A mediated breast cancer angiogenesis in normoxia and participates in a positive feedback loop with HIF1A in hypoxia.

BACKGROUND: The eukaryotic elongation factor, EEF1A2, has been identified as an oncogene in various solid tumors. Here, we have identified a novel function of EEF1A2 in angiogenesis. METHODS: Chick chorioallantoic membrane, tubulogenesis, aortic ring, Matrigel plug, and skin wound healing assays established EEF1A2's role in angiogenesis. RESULT: Higher EEF1A2 levels in breast cancer cells enhanced cell growth, movement, blood vessel function, and tubule formation in HUVECs, as confirmed by ex-ovo and in-vivo tests. The overexpression of EEF1A2 could be counteracted by Plitidepsin. Under normoxic conditions, EEF1A2 triggered HIF1A expression via ERK-Myc and mTOR signaling in TNBC and ER/PR positive cells. Hypoxia induced the expression of EEF1A2, leading to a positive feedback loop between EEF1A2 and HIF1A. Luciferase assay and EMSA confirmed HIF1A binding on the EEF1A2 promoter, which induced its transcription. RT-PCR and polysome profiling validated that EEF1A2 affected VEGF transcription and translation positively. This led to increased VEGF release from breast cancer cells, activating ERK and PI3K-AKT signaling in endothelial cells. Breast cancer tissues with elevated EEF1A2 showed higher microvessel density. CONCLUSION: EEF1A2 exhibits angiogenic potential in both normoxic and hypoxic conditions, underscoring its dual role in promoting EMT and angiogenesis, rendering it a promising target for cancer therapy.

IQ Motif-Containing GTPase-Activating Protein 2 Inhibits Breast Cancer Angiogenesis by Suppressing VEGFR2-AKT Signaling.

Antiangiogenesis cancer therapies are facing setbacks due to side effects and resistance. Parallel targeting of multiple pathways can help in the development of more effective therapies. This requires the discovery of new molecules that can regulate multiple cellular processes. Our study has recently established the association of reduced IQGAP2 expression in breast cancer with EMT and poor prognosis of the patient. Existing literature indirectly suggests the role of IQGAP2 in angiogenesis that is still unexplored. In this study, we searched the role of IQGAP2 in tumor angiogenesis in a comprehensive manner using cell culture, patients, and animal models. Depletion of IQGAP2 in breast cancer cells increased proliferation, migration, and tubulogenesis of HUVECs. Findings were validated in ex ovo CAM, Matrigel plug and skin wound-healing assays in mouse model, showing that the reduction of IQGAP2 significantly increased angiogenesis. As a confirmation, IHC analysis of the patient's tissues showed a negative correlation of IQGAP2 expression with the microvessel density. Mechanistically, loss of IQGAP2 appeared to activate VEGF-A via ERK activation in tumor cells, which activated the VEGFR2-AKT axis in HUVECs. IMPLICATIONS: The findings of this study suggest the antiangiogenic properties of IQGAP2 in breast cancer. The Dual effect of IQGAP2 on EMT and angiogenesis makes it a potential target for anticancer therapy.

Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status.

IQGAP2, a member of the IQGAP family, functions as a tumor suppressor in most of the cancers. Unlike IQGAP1 and IQGAP3, which function as oncogenes in breast cancer, the role of IQGAP2 is still unexplored. Here we report a reduced expression of IQGAP2, which was associated with lymph node positivity, lymphovascular invasion, and higher age in breast cancer patients. We found an inverse correlation of IQGAP2 expression levels with oncogenic properties of breast cancer cell lines in estrogen receptor (ER) independent manner. IQGAP2 expression enhanced apoptosis via reactive oxygen species (ROS)-P38-p53 pathway and reduced epithelial-mesenchymal transition (EMT) in a MEK-ERK-dependent manner. IQGAP2-IQGAP1 ratio correlated negatively with phospho-ERK levels in breast cancer patients. Pull-down assay showed interaction of IQGAP1 and IQGAP2. IQGAP2 overexpression rescued, IQGAP1-mediated ERK activation, suggesting the possibility of IQGAP1 sequestration by IQGAP2. IQGAP2 depletion, in a tumor xenograft model, increased tumor volume, tumor weight, and phospho-ERK expression. Overall, our findings suggest that IQGAP2 is negatively associated with proliferative and metastatic abilities of breast cancer cells. Suppression of IQGAP1-mediated ERK activation is a possible route via which IQGAP2 restricts oncogenic properties of breast cancer cells. Our study highlights the candidature of IQGAP2 as a potent target for therapeutic intervention.

Expression pattern of EEF1A2 in brain tumors: Histological analysis and functional role as a promoter of EMT.

AIMS: Glioblastomas are highly aggressive brain tumors with a very poor survival rate. EEF1A2, the proto-oncogenic isoform of the EEF1A translation factor family, has been found to be overexpressed and promoting tumorigenesis in multiple cancers. Interestingly, recent studies reported reduced expression of this protein in brain tumors, drawing our attention to find the functional role and mechanism of this protein in brain tumor progression. MAIN METHODS: Using representative cell line as models, the role of EEF1A2 in cell proliferation, migration and invasion were assessed using MTS assay, scratch wound-healing assay, transwell migration and invasion assay, respectively. Activation of key signaling pathways was assessed using western blots and real-time PCR. Finally, using immunohistochemistry we checked the protein levels of EEF1A2 in CNS tumors. KEY FINDINGS: EEF1A2 was found to increase the proliferative, migratory and invasive properties of cell lines of both glial and neuronal origin. PI3K activation directly correlated with EEF1A2 levels. Protein levels of key EMT markers viz. Twist, Snail, and Slug were increased upon ectopic EEF1A2 expression. Furthermore, EEF1A2 was found to affect the expression levels of key inflammatory cytokines, growth factors and matrix metalloproteases. IHC analysis showed that EEF1A2 is upregulated in tumor tissues compared to normal tissue. SIGNIFICANCE: EEF1A2 acts as an oncogene in both neuronal and glial cells and triggers an EMT program via PI3K pathway. However, it shows enhanced expression in neuronal cells of the brain than the glial cells, which could explain the previously reported anomaly.

Reduced expression of IQGAP2 and higher expression of IQGAP3 correlates with poor prognosis in cancers.

IQGAPs is a family of proteins which comprises three members, in humans. The expression pattern and role of IQGAP1 has been well established in many cancers, whereas those of IQGAP2 and IQGAP3, have mostly remained unexplored. We used available large datasets, to explore the pan-cancer status of these two genes in-silico. Here we have analysed their mRNA expression and correlation with survivability in eight different cancers, including lung, breast, gastric, brain, colorectal, prostate, liver and kidney cancers and, their subtypes. The mRNA expression of IQGAP2 and IQGAP3 in individual cancers were analysed in two different publicly available databases viz. Oncomine and TCGA. The prognostic value of these genes in lung, breast and gastric cancer was analysed using Kaplan-Meier Plotter database, whereas for brain, colorectal, liver, prostate and kidney cancers, SurvExpress database was used. These results were validated by immunohistochemistry in cancer tissues (stomach, prostate, brain, colorectal). Moreover, we did IQGAP2 and IQGAP3 genomic alteration and, promoter methylation analysis using cBioportal and Wanderer web tool, respectively. Most of the cancer types (lung, breast, prostate, brain, gastric, liver, kidney and colorectal) showed increased IQGAP3 mRNA expression. In contrast, the IQGAP2 transcript levels were reduced across different cancers viz. lung, breast, gastric, liver, kidney and colorectal cancer. IQGAP2 expression correlated positively with survivability, on the contrary, IQGAP3 expression levels correlated inversely with survivability, in most of the cancers. Collectively, enhanced IQGAP3 and reduced IQGAP2 levels were frequently observed in multiple cancers with the former predicting poor survivability and the later opposite. Methylation pattern was significantly altered in most of the cancer types. We found copy no. variation and mutations in specific cancers, for IQGAP2 and IQGAP3. Our in-vivo (IHC) data confirmed the in-silico findings completely. Hence, IQGAP2 and IQGAP3 have potential to be used as prognostic markers or therapeutic targets in specific cancers.

Intramuscular Arteriovenous Hemangioma of Thigh: A Case Report and Review of Literature.

INTRODUCTION: Skeletal muscle hemangiomas are uncommon soft tissue tumors; more than 90% are misdiagnosed initially. They present as chronic pain and swelling in a muscle with or without a history of trauma. Magnetic resonance imaging is the investigation of choice. Many treatment modalities for the symptomatic hemangiomas are available of which surgical excision is the most preferred. CASE REPORT: We present an unusual case of pain, swelling, and restriction of movements in the right knee following an episode of trauma in an 8-year-old boy diagnosed to have intramuscular arteriovenous hemangioma in the vastusmedialis and vastusintermedius for which he was treated by surgical excision and followed for 2 years and found to have no recurrence. CONCLUSION: Skeletal muscle hemangiomas are completely treatable; the knowledge of their natural history, clinical findings, and imaging appearances are of great importance for proper diagnosis and treatment.

Clinico-Pathological Correlation of ß-Catenin and Telomere Dysfunction in Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: Tumorigenesis is a complex process of accumulated alteration in function of multiple genes and pathways. Wnt signalling pathway is involved in various differentiation events during embryonic development and is conserved in various species. OBJECTIVE: A multicentre collaborative initiative is undertaken to study the occurrence, prognosis and molecular mechanism of HNSCC (Head and Neck Squamous Cell Carcinoma) which is highly prevalent in eastern parts of India. From a large cohort of HNSCC tissue repository, 67 cases were selected for multi-parametric investigation. RESULTS: 67 cases showed stable ß-catenin expression. We have seen correlation, if any, of the transcription factor - ß-catenin, telomere maintenance and shelterin complex proteins - TRF2, Rap1 and hTert with respect to tumor differentiation and telomere dysfunction. Immunohistochemistry of ß-catenin protein showed stable and high expression in tumor when compared to stroma. MDSCC (Moderately Differentiated Squamous cell carcinoma) cases expressed nuclear expression of ß-catenin in invasive fronts and showed increased genomic instability. Higher frequency of Anaphase bridges was observed ranging from <3% in normal cut margin to 13% in WDSCC (Well differentiated squamous cell carcinoma) and 18% in MDSCC (Moderately differentiated Squamous cell carcinoma). There was significant decrease in telomere length in MDSCC (<4) when compared to the normal cut margin samples (<7). Quantitative Real Time-PCR confirmed a significant correlationship between stable ß-catenin expression and poor clinical and pathological outcome. CONCLUSION: The Stabilisation and accumulation of ß-catenin was significant and correlated well with de-differentiation process as well as prognosis and therapy outcome of the patients in the cohort. Expression status of molecular markers such as ß-catenin, hTert, TRF2 and RAP1 correlate significantly with the process of tumorigenesis and prognosis and may play a role in therapeutic management of Head and neck patients.

Malignant peripheral nerve sheath tumor of adrenal gland with heterologus osseous differentiation in a case of Von Recklinghausen's disease.

Malignant peripheral nerve sheath tumor (MPNST) of the adrenal gland is extremely rare. Most of them occur in association with neurofibromatosis, ganglioneuroma or as part of a composite tumor such as pheochromocytoma. Only seven cases of MPNST of the adrenal gland have been reported in the literature till date. Discriminating this entity from other soft tissue sarcomas and gastrointestinal stromal tumor of the adrenal gland has important diagnostic and therapeutic implications. Moreover, the tumor size and pattern of expression for certain immunohistochemical markers may serve as independent predictors of aggressiveness. Herein we present a 24-years-old male with features of Von Recklinghausen's disease who presented with large left adrenal gland malignant peripheral nerve sheath tumor.

Aggressive angiomyxoma presenting as a vulval polyp.

Aggressive angiomyxoma is a rare, locally invasive mesenchymal tumor, occurring predominantly in the pelvic-perineal region of adults and carries a high risk for local relapse and hence the need to differentiate it from the other mesenchymal tumors occurring in this region. Presentation as a pedunculated polyp, like in our case, is unusual for this rare tumor. Except for positive surgical margins, there are no clinical or histological means for predicting the tumor recurrence. A diligent long-term follow-up is mandatory. Though rare, this tumor needs to be considered in the differential diagnosis of vulval polyps.

Embryonal sarcoma of liver: an undifferentiated rare primary solid and mucoid to cystic tumour.

Undifferentiated (embryonal) sarcoma of the liver is a rare primary malignant tumor of the liver occurring almost exclusively in childhood with characterisitic findings on gross and microscopy. Careful sampling of the tumor shows various immature undifferentiated elements and infiltration of the tumor into the surrounding capsule. CT findings could be suggestive of a hamartoma, as in our case. We report a case of hepatic embryonal sarcoma in a ten-year old male child presenting with an abdominal mass.