Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Alternative splicing of mRNA precursors enables one gene to produce multiple protein isoforms with differing functions. Under normal conditions, this mechanism is tightly regulated in order for the human genome to generate proteomic diversity sufficient for the functional requirements of complex tissues. When deregulated, however, cancer cells take advantage of this mechanism to produce aberrant proteins with added, deleted, or altered functional domains that contribute to tumorigenesis. Here, we discuss aspects of alternative splicing misregulation in cancer, focusing on splicing events affected by deregulation of regulatory splicing factors and also recent studies identifying mutated components of the splicing machinery.

Significance: An increasing body of evidence indicates that aberrant splicing of mRNA precursors leads to production of aberrant proteins that contribute to tumorigenesis. Recent studies show that alterations in cellular concentrations of regulatory splicing factors and mutations in components of the core splicing machinery provide major mechanisms of misregulation of mRNA splicing in cancer. A better understanding of this misregulation will potentially reveal a group of novel drug targets for therapeutic intervention. Cancer Discov; 3(11); 1228–37. ©2013 AACR .

https://cancerdiscovery.aacrjournals.org/content/candisc/3/11/1228.full.pdf

Misregulation of pre-mRNA alternative splicing in cancer.

Post-transcriptional modifications, such as 5' end capping, 3' end polyadenylation and splicing, are necessary for the precise regulation of gene expression and transcriptome integrity. Therefore, it is not surprising that abnormalities of these post-transcriptional modifications prompt numerous diseases, including cancer. In fact, many studies revealed that misregulation of mRNA processing, especially splicing, are observed in a variety of cancer cells. In this review we describe how changes within RNA splicing regulatory elements or mutations in the processing factors alter the expression of tumor suppressors or oncogenes with pathological consequences. In addition, we show how several small molecules that bind to spliceosomal components and splicing regulators inhibit or modulate splicing activity. These compounds have anticancer activity and further development of small molecule modulators has potential in next generation cancer therapy.

Splicing in oncogenesis and tumor suppression.

The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041). These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC.

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Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

Background
It is well-known that the treatment and monitoring methods are limited for advanced stage of endometrial carcinoma. Biological molecules with expression changes during tumor progression become potential therapeutic targets for advanced stage endometrial carcinoma. Annexin A2 (ANXA2) has been reported to be overexpressed in recurrent endometrial carcinoma, and the expression of human epididymis protein 4 (HE4) is upregulated in endometrial carcinoma. What’s more, ANXA2 and HE4 interacted in ovarian cancer and promoted the malignant biological behavior. We speculated that their interaction may exist in endometrial carcinoma as well. We evaluated the expression and the correlation relationship of ANXA2 and HE4 in endometrial carcinoma.

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Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma

Osteosarcoma (OS) is the most common primary malignant bone sarcoma mainly affecting adolescents and young adults, which often progresses to pulmonary metastasis and leads to the death of OS patients. OS is characterized as a highly heterogeneous cancer type and the underlying pathologic mechanisms triggering tumor progress and metastasis are incompletely recognized. Surgery combined with neoadjuvant and postoperative chemotherapy has elevated 5-year survival to over 70% for patients with localized OS tumors, as opposed to only 20% of patients with recurrence and/or metastasis. Therefore, novel therapeutic strategies are needed to overcome the drawbacks of conventional treatments. Immunotherapy is gaining momentum for the treatment of OS with an increasing number of FDA-approved therapies for malignancies resistant to conventional therapies. Here, we review the OS tumor microenvironment and appraise the promising immunotherapies available in the management of OS.

/pdf/novel-immunotherapies-for-osteosarcoma-1xz7jh5t.pdf

Novel Immunotherapies for Osteosarcoma

To explore the roles of Bcl-xl and Bcl-xs in the development and progression of endometrial carcinoma, and to analyze the correlation between Bcl-xl and Bcl-xs. RT-PCR and Western-blot assay were applied to detect the expressions of Bcl-xl and Bcl-xs in endometrial tissues of various histomorphologic types. The Bcl-xl expression levels of simple and atypical hyperplasia endometrial tissues were not significantly different from that of normal endometrial tissue (both P > 0.05). On contrary, Bcl-xl expression in endometrial carcinoma tissue was significantly higher than the normal endometrial tissue (P = 0.00), which was correlated with the pathological grading of endometrial carcinoma (F = 5.33, P = 0.02). In addition, Bcl-xs mRNA level in simple hyperplasia endometrial tissue had no significant difference compared to that in normal endometrial tissue (P = 0.12), while the levels of atypical hyperplasia and endometrial carcinoma endometrial tissues were significantly different from the normal endometrial tissue (both P = 0.00). Furthermore, level of Bcl-xs mRNA was correlated with the clinical staging and lymph node metastasis of the endometrial carcinoma (P < 0.05). The expressions of Bcl-xl and Bcl-xs were negatively correlated with each other (r = -0.76). The abnormal expressions of Bcl-xs and Bcl-xl were one of the molecular mechanisms for the pathogenesis of endometrial carcinoma, and altered ratio between these two might involve in the onset of endometrial carcinoma.

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Relevance of Bcl-x expression in different types of endometrial tissues

To investigate the role of HER-2/neu-mediated COX-2/P450arom signal in estrogen-dependent endometrial carcinoma. The recombinant eukaryotic expression vector, pcDNA3.1-HER-2/neu, was constructed and transfect to Ishikawa endometrial carcinoma cells. The expression of COX-2 and P450arom in transfected cells were detected by real-time PCR and western blotting. The levels of estrogen in cell supernatants were detected by ELISA. Over-expression of HER-2/neu in transfected cells was confirmed by real-time PCR and western blotting. The levels of autocrine estrogen in transfected cells was significantly increased which combination with the enhancement of COX-2 and P450arom expression in transfected cells. HER-2/neu induced the improvement of autocrine estrogen in endometrial carcinoma cell through triggering the COX-2/P450arom signal.

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Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells

Yuanqi He

Papers

Novel Immunotherapies for Osteosarcoma

Relevance of Bcl-x expression in different types of endometrial tissues

Effects of ectopic HER-2/neu gene expression on the COX-2/PGE2/P450arom signaling pathway in endometrial carcinoma cells: HER-2/neu gene expression in endometrial carcinoma cells