Transcriptional repression of tumor suppressor CDC73, encoding an RNA polymerase II interactor, by Wilms tumor 1 protein (WT1) promotes cell proliferation: implication for cancer therapeutics.

The Wilms tumor 1 gene (WT1) can either repress or induce the expression of genes. Inconsistent with its tumor suppressor role, elevated WT1 levels have been observed in leukemia and solid tumors. WT1 has also been suggested to act as an oncogene by inducing the expression of MYC and BCL-2. However, these are only the correlational studies, and no functional study has been performed to date. Consistent with its tumor suppressor role, CDC73 binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex and causes transcriptional repression of oncogenes MYC and CCND1. It also represses ß-catenin-mediated transcription. Based on the reduced level of CDC73 in oral squamous cell carcinoma (OSCC) samples in the absence of loss-of-heterozygosity, promoter methylation, and mutations, we speculated that an inhibitory transcription factor is regulating its expression. The bioinformatics analysis predicted WT1 as an inhibitory transcription factor to regulate the CDC73 level. Our results showed that overexpression of WT1 decreased CDC73 levels and promoted proliferation of OSCC cells. ChIP and EMSA results demonstrated binding of WT1 to the CDC73 promoter. The 5-azacytidine treatment of OSCC cells led to an up-regulation of WT1 with a concomitant down-regulation of CDC73, further suggesting regulation of CDC73 by WT1. Exogenous CDC73 attenuated the protumorigenic activity of WT1 by apoptosis induction. An inverse correlation between expression levels of CDC73 and WT1 was observed in OSCC samples. These observations indicated that WT1 functions as an oncogene by repressing the expression of CDC73 in OSCC. We suggest that targeting WT1 could be a therapeutic strategy for cancer, including OSCC.

Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics.

The CDC73 gene is mutationally inactivated in hereditary and sporadic parathyroid tumors. It negatively regulates ß-catenin, cyclin D1, and c-MYC. Down-regulation of CDC73 has been reported in breast, renal, and gastric carcinomas. However, the reports regarding the role of CDC73 in oral squamous cell carcinoma (OSCC) are lacking. In this study we show that CDC73 is down-regulated in a majority of OSCC samples. We further show that oncogenic microRNA-155 (miR-155) negatively regulates CDC73 expression. Our experiments show that the dramatic up-regulation of miR-155 is an exclusive mechanism for down-regulation of CDC73 in a panel of human cell lines and a subset of OSCC patient samples in the absence of loss of heterozygosity, mutations, and promoter methylation. Ectopic expression of miR-155 in HEK293 cells dramatically reduced CDC73 levels, enhanced cell viability, and decreased apoptosis. Conversely, the delivery of a miR-155 antagonist (antagomir-155) to KB cells overexpressing miR-155 resulted in increased CDC73 levels, decreased cell viability, increased apoptosis, and marked regression of xenografts in nude mice. Cotransfection of miR-155 with CDC73 in HEK293 cells abrogated its pro-oncogenic effect. Reduced cell proliferation and increased apoptosis of KB cells were dependent on the presence or absence of the 3'-UTR in CDC73. In summary, knockdown of CDC73 expression due to overexpression of miR-155 not only adds a novelty to the list of mechanisms responsible for its down-regulation in different tumors, but the restoration of CDC73 levels by the use of antagomir-155 may also have an important role in therapeutic intervention of cancers, including OSCC.

Anti-NMDAR limbic encephalitis--a clinical curiosity.

BACKGROUND: Neurological paraneoplastic syndromes are rarely the first manifestation of an underlying cancer. A high index of suspicion is thus needed to diagnose such conditions. Paraneoplastic limbic encephalitis is one such entity which is well described in association with small cell lung cancers, testicular germ cell tumors, breast cancers and ovarian tumors. This article describes the entity being associated with an ovarian tumor. CASE: A 36-year-old female presented with abnormal behaviour, mood swings and delusions. She was evaluated for her psychiatric symptoms and found to have an underlying ovarian tumor. Anti-NMDA receptor titers were strongly positive. She underwent oophorectomy, and post-operatively there was a significant improvement in her psychiatric symptoms. CONCLUSIONS: Ovarian tumors like teratomas are implicated in the pathogenesis of paraneoplastic limbic encephalitis. An underlying ovarian tumor must be evaluated in all young females presenting with sudden onset of psychiatric symptoms.

Versatility of Rectus Abdominis Myocutaneous Flap in Primary Reconstruction of Defects in Surgical Oncology.

With the advent of microvascular surgery, the choice of reconstruction following resection of the primary has an important bearing on the final functional and cosmetic outcome in surgical oncology. The vertical rectus abdominis myocutaneous (VRAM) flap is arguably the most widely used and versatile flap in reconstructive surgery. All patients undergoing a VRAM flap reconstruction following resection of their tumor in the Surgical Oncology Department of a tertiary cancer center from 2012 to 2019 were included in the study. Defects ranged from the breast (40), head and neck (10), groin (3), and perineum (5). The primary outcome measure was incidence of complete and partial flap necrosis, while incidence of hematoma, seroma, incisional hernia, wound dehiscence, and infection were secondary outcomes measured. The patients were followed up for a minimum period of 1 year. The incidence of complete flap necrosis was 5.1% (3) and partial loss 12% (7). Incidence of minor complications such as seroma was 13.7% (8), hematoma 6.8% (4), wound dehiscence 10.3% (6), and wound infection 5.1% (3). Incisional hernia and donor site wound-related complications were not seen in any. On binary regression analysis, the presence of diabetes mellitus, smoking, and the use of adjuvant treatment were associated significantly with increased odds of flap loss. This study demonstrates the versatility and reliability of the VRAM flap in primary reconstruction of defects in surgical oncology. Optimization of risk factors such as diabetes, smoking, and weight gain can reduce flap loss and improve outcomes.

Author Correction: Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Metachronous Synchronous Sternal and Colonic Metastasis with Asymptomatic Colo-colic Fistula from Carcinoma Ovary Rare Presentation of Ovarian Cancer.

Ovarian cancer is one of the most common gynecological cancers worldwide. It is the third leading cause of cancer among women in India. Metastatic disease to the visceral organs from ovarian cancer occurs as a terminal event in the natural history of the disease. In particular, spread to the bone and large bowel is infrequently described. The risk of distant metastasis increases in a recurrent setting. We describe a case of a 77-year-old lady, who was diagnosed for ovarian carcinoma in 2007 and underwent primary cytoreductive surgery, stage IIIc. She presented to us with asymptomatic rising cancer antigen (CA) 125 levels during follow-up. On evaluation she was found to have sternal and colonic deposits. She underwent left hemicolectomy and biopsy of sternal deposit. Histopathology revealed metastasis from the carcinoma ovary to the colon and sternum. This case report highlights the rare synchronous metastatic disease in a metachronous setting from ovarian carcinoma.

Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo.

The ESRRA gene encodes a transcription factor and regulates several genes, such as WNT11 and OPN, involved in tumorigenesis. It is upregulated in several cancers, including OSCC. We have previously shown that the tumor suppressor miR-125a targets ESRRA, and its downregulation causes upregulation of ESRRA in OSCC. Upregulation of ESRRA in the absence of downregulation of miR-125a in a subset of OSCC samples suggests the involvement of an alternative mechanism. Using TaqMan(®) copy number assay, here we report for the first time that the genomic amplification of ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage-independent cell growth and invasion, and inhibited apoptosis. Whereas, knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage-independent cell growth and invasion, and accelerated apoptosis. Furthermore, the delivery of a synthetic biostable ESRRA siRNA to OSCC cells resulted in regression of xenografts in nude mice. Thus, the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers.

Isolated nasopharyngeal metastasis from hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, the incidence of which parallels that of areas with high prevalence of chronic hepatitis. HCC commonly metastasizes to the lungs, lymph nodes, adrenals and bones with the overall prognosis of metastatic HCC being dismal. PRESENTATION OF CASE: We herein with present a case of a 70-year-old male who was referred to our institution with history of nasal obstruction and nasal bleeding which on further evaluation was diagnosed to have an isolated metastasis to nasopharynx from liver primary. DISCUSSION: Extrahepatic metastasis in HCC occurs in about 30-50% of patients, the commonest site being the lung. Rare sites of extrahepatic metastasis from HCC to the ovaries, kidneys, skeletal and cardiac musculature and brain have been reported. Unusual sites of metastasis in the head and neck area like the mandible have also been documented. With the changing trends in the treatment modalities, these patients are often treated using target therapy. CONCLUSION: This article presents an unusual isolated metastasis to nasopharynx from HCC in the absence of disseminated disease. This case report illustrates the distinctive pathological features of metastatic HCC.

Primary microcephaly gene MCPH1 shows signatures of tumor suppressors and is regulated by miR-27a in oral squamous cell carcinoma.

Mutations in the MCPH1 (microcephalin 1) gene, located at chromosome 8p23.1, result in two autosomal recessive disorders: primary microcephaly and premature chromosome condensation syndrome. MCPH1 has also been shown to be downregulated in breast, prostate and ovarian cancers, and mutated in 1/10 breast and 5/41 endometrial tumors, suggesting that it could also function as a tumor suppressor (TS) gene. To test the possibility of MCPH1 as a TS gene, we first performed LOH study in a panel of 81 matched normal oral tissues and oral squamous cell carcinoma (OSCC) samples, and observed that 14/71 (19.72%) informative samples showed LOH, a hallmark of TS genes. Three protein truncating mutations were identified in 1/15 OSCC samples and 2/5 cancer cell lines. MCPH1 was downregulated at both the transcript and protein levels in 21/41 (51.22%) and 19/25 (76%) OSCC samples respectively. A low level of MCPH1 promoter methylation was also observed in 4/40 (10%) tumor samples. We further observed that overexpression of MCPH1 decreased cellular proliferation, anchorage-independent growth in soft agar, cell invasion and tumor size in nude mice, indicating its tumor suppressive function. Using bioinformatic approaches and luciferase assay, we showed that the 3'-UTR of MCPH1 harbors two non-overlapping functional seed regions for miR-27a which negatively regulated its level. The expression level of miR-27a negatively correlated with the MCPH1 protein level in OSCC. Our study indicates for the first time that, in addition to its role in brain development, MCPH1 also functions as a tumor suppressor gene and is regulated by miR-27a.