Loss of miR-936 leads to acquisition of androgen-independent metastatic phenotype in prostate cancer.

Prostate cancer (PCa) progresses from a hormone-sensitive, androgen-dependent to a hormone-refractory, androgen-independent metastatic phenotype. Among the many genes implicated, ANXA2, a calcium-dependent phospholipid binding protein, has been found to have a critical role in the progression of PCa into more invasive metastatic phenotype. However, the molecular mechanisms underlying the absence of ANXA2 in early PCa and its recurrence in advanced stage are yet unknown. Moreover, recent studies have observed the deregulation of microRNAs (miRNAs) are involved in the development and progression of PCa. In this study, we found the down-regulation of miR-936 in metastatic PCa wherein its target ANXA2 was overexpressed. Subsequently, it has been shown that the downregulation of miRNA biogenesis by siRNA treatment in ANXA2-null LNCaP cells could induce the expression of ANXA2, indicating the miRNA mediated regulation of ANXA2 expression. Additionally, we demonstrate that miR-936 regulates ANXA2 expression by direct interaction at coding as well as 3'UTR region of ANXA2 mRNA by luciferase reporter assay. Furthermore, the overexpression of miR-936 suppresses the cell proliferation, cell cycle progression, cell migration, and invasion abilities of metastatic PCa PC-3 cells in vitro and tumor forming ability in vivo. These results indicate that miR-936 have tumor suppressor properties by regulating the over expression of ANXA2 in hormone-independent metastatic PCa. Moreover, our results suggest that this tumor suppressor miR-936 could be developed as a targeted therapeutic molecule for metastatic PCa control and to improve the prognosis in PCa patients.

Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.

Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.

Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4.

Elevated glycemic index, an important feature of diabetes is implicated in an increased risk of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of this association are relatively less explored. Present study investigates the effect of hyperglycemia over HCC proliferation. We observed that high glucose culture condition (HG) specifically activates canonical Wnt signaling in HCC cells, which is mediated by suppression of DKK4 (a Wnt antagonist) expression and enhanced ß-catenin level. Functional assays demonstrated that a normoglycemic culture condition (NG) maintains constitutive expression of DKK4, which controls HCC proliferation rate by suppressing canonical Wnt signaling pathway. HG diminishes DKK4 expression leading to loss of check at G0/G1/S phases of the cell cycle thereby enhancing HCC proliferation, in a ß-catenin dependent manner. Interestingly, in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of ß-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose facilitated HCC proliferation.

Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.

Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.

Synchronous bilateral medullary carcinoma of breast: is it metastasis or second primary?

Bilateral breast cancer is a rare event accounting for 2-5% of all breast malignancies. A second tumor in contralateral breast may be either synchronous or metachronous lesion. Synchronous bilateral invasive ductal carcinoma is known but medullary carcinoma is rare. The etiology of bilateral breast cancer is uncertain and prognosis in these cases once thought to be poor but recent data suggest a similar survival compared to unilateral disease. We report a case of triple negative synchronous bilateral medullary carcinoma in a 38-year-old female who presented with lump in both the breasts for three months. Multidetector computed tomography breast scan revealed bilateral heterogeneously enhancing well-defined lesion in both the breasts. Fine needle aspiration cytology from both the breast lump was suggestive of malignancy. Patient underwent bilateral modified radical mastectomy with axillary clearance in a single sitting. Histopathology showed synchronous bilateral medullary carcinoma of breast with ER, PR and HER- 2/ neu negativity. Patient was treated with chemoradiation and she is on regular follow up for one year without any recurrence or metastasis.

Glomus tumor of the nail unit.

Glomus tumor is a benign tumor arising from the neuromyoarterial plexus concentrated beneath the nail. This plexus is an arteriovenous anastomosis functioning without the intermediary capillary bed. Etiology is not exactly known. It is debilitating to the patient because of the chronicity of symptoms and lack of proper investigation which will help in identifying the tumor at an early stage. We report a case of glomus tumor situated in the proximal nail fold region and causing longitudinal splitting of nail.

Subcutaneous human dirofilariasis due to dirofilaria repens: report of two cases.

Zoonotic filariasis due to Dirofilaria repens (D. repens) is prevalent in several regions of the world. In view of recent rise of human D. repens infections in Europe, Africa and Asia, it is considered an emerging zoonosis in these continents. Most of the documented cases of human dirofilariasis recorded in India had ocular infections, but very few subcutaneous dirofilariasis have been reported. We hereby report two cases of subcutaneous human dirofilariasis due to D.repens with varied clinical presentations.

Accidental ingestion of a barbed wire broach and its endoscopic retrieval: prevention better than cure.

Ingestion of instruments is a potential complication that can occur during dental procedures. We report a case of accidental ingestion of an endodontic barbed wire broach during root canal treatment and its subsequent retrieval by endoscopic methods. Although prevention is the best approach, proper management of such an event is also crucial. The objective of this report is to draw attention to the potentially serious complications that can occur if preventive techniques are not practised, and to discuss the accepted guidelines for management of such an event.

Transabdominal impalement: absence of visceral or vascular injury a rare possibility.

BACKGROUND: Abdominal impalement injuries are usually associated with visceral and vascular injury, causing significant morbidity and mortality. The management of these injuries poses specific challenges in prehospital care, transport, and management strategies. OBJECTIVE: We report a case of transabdominal impalement with no injury to intra-abdominal visceral or vascular structures, demonstrating a chance occurrence. The literature regarding abdominal impalement injury is reviewed and the management of these injuries is discussed. CASE REPORT: A 35-year-old man with a transabdominal impalement injury after an accidental fall from a tree on to a wooden fence was brought to the Accident and Emergency Department. The wooden fence piece was impaled and in situ. Laparotomy revealed no intra-abdominal visceral or vascular injury. CONCLUSION: Transabdominal impalement injuries pose peculiar challenges in prehospital care, transport to hospital, and management. Operative intervention is required in all cases for a conclusive and safe management, as the possibility of escaping intra-abdominal injury is very rare.