Overexpression of splicing factor poly(rC)-binding protein 1 elicits cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells.

PURPOSE: Splicing factor poly(rC)-binding protein 1 (PCBP1) is a novel tumor suppressor that is downregulated in several cancers thereby regulating tumor formation and metastasis. However, the involvement of PCBP1 in apoptosis of cancer cells and the molecular mechanism remains elusive. On this basis, we sought to investigate the role of splicing factor PCBP1 in the apoptosis in human cervical cancer cells. METHODS: To investigate PCBP1 functions in vitro, we overexpressed PCBP1 in human cervical cancer cells. A series of cytological function assays were employed to study to the role of PCBP1 in cell proliferation, cell cycle arrest and apoptosis. RESULTS: Overexpression of PCBP1 was found to greatly repress proliferation of HeLa cells in a time-dependent manner. It also induced a significant increase in G2/M phase arrest and apoptosis. Furthermore, overexpressed PCBP1 favored the production of long isoforms of p73, thereby inducing upregulated ratio of Bax/Bcl-2, the release of cytochrome c and the expression of caspase-3. CONCLUSION: Our results revealed that PCBP1 played a vital role in p73 splicing, cycle arrest and apoptosis induction in human cervical carcinoma cells. Targeting PCBP1 may be a potential therapeutic strategy for cervical cancer therapy.

RNA-binding protein 39: a promising therapeutic target for cancer.

RNA-binding motif protein 39 (RBM39), as a key factor in tumor-targeted mRNA and protein expression, not only plays a vital role in tumorigenesis, but also has broad development prospects in clinical treatment and drug research. Moreover, since RBM39 was identified as a target of sulfonamides, it has played a key role in the emerging field of molecule drug development. Hence, it is of great significance to study the interaction between RBM39 and tumors and the clinical application of drug-targeted therapy. In this paper, we describe the possible multi-level regulation of RBM39, including gene transcription, protein translation, and alternative splicing. Importantly, the molecular function of RBM39 as an important splicing factor in most common tumors is systematically outlined. Furthermore, we briefly introduce RBM39's tumor-targeted drug research and its clinical application, hoping to give reference significance for the molecular mechanism of RBM39 in tumors, and provide reliable ideas for in-depth research for future therapeutic strategies.

Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation.

Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development.

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

Multilevel regulation and molecular mechanism of poly (rC)-binding protein 1 in cancer.

Poly (rC)-binding protein 1 (PCBP1), an RNA- or DNA-binding protein with a relative molecular weight of 38 kDa, which is characterized by downregulation in many cancer types. Numerous cases have indicated that PCBP1 could be considered as a tumor suppressor to inhibit tumorigenesis, development, and metastasis. In the current review, we described the multilevel regulatory roles of PCBP1, including gene transcription, alternative splicing, and translation of many cancer-related genes. Additionally, we also provided a brief overview about the inhibitory effect of PCBP1 on most common tumors. More importantly, we summarized the current research status about PCBP1 in hypoxic microenvironment, autophagy, apoptosis, and chemotherapy of cancer cells, aiming to clarify the molecular mechanisms of PCBP1 in cancer. Taken together, in-depth study of PCBP1 in cancer may provide new ideas for cancer therapy.

Transforming growth factor ß signaling pathway: A promising therapeutic target for cancer.

Transforming growth factor ß (TGF-ß) is part of the transforming growth factor ß superfamily which is involved in many physiological processes and closely related to the carcinogenesis. Here, we discuss the TGF-ß structure, function, and its canonical Smads signaling pathway. Importantly, TGF-ß has been proved that it plays both tumor suppressor as well as an activator role in tumor progression. In an early stage, TGF-ß inhibits cell proliferation and is involved in cell apoptosis. In an advanced tumor, TGF-ß signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial-mesenchymal transition, and immune escape. Furthermore, we are centered on updated research results into the inhibitors as drugs which have been studied in preclinical or clinical trials in tumor carcinogenesis to prevent the TGF-ß synthesis and block its signaling pathways such as antibodies, antisense molecules, and small-molecule tyrosine kinase inhibitors. Thus, it is highlighting the crucial role of TGF-ß in tumor therapy and may provide opportunities for the new antitumor strategies in patients with cancer.