Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers

Ullah, Irfan; Sun, Weichao; Tang, Liling; Feng, Jianguo

doi:10.7150/jca.20906

Cited by 29 publications

(27 citation statements)

References 94 publications

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“…TGF‐β signals are transduced by the SMAD family that regulates homeostasis, proliferation, apoptosis, differentiation and tumor growth. SMAD4 functions as a shuttle between the cytoplasm and the nucleus, whose gene is located on the long arm of chromosome 18 at point 21.1 14,44,45 (Figure 2).…”

Section: Mir‐145 In Drug Resistancementioning

confidence: 99%

“…MiR‐145 increased the doxorubicin cytotoxicity in chemoresistant tumor cells via EMT through downregulating SMAD3 in HCC 15 . SMAD3, another member of the SMAD family, serves as a substrate for TGF‐β and commonly called receptor‐regulated SMAD 44,70 . Tumor suppressor miR‐145 reversed 5‐FU resistance by directly targeting DNA damage‐related gene RAD18 in CRC.…”

Section: Mir‐145 In Drug Resistancementioning

confidence: 99%

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MiR‐145 in cancer therapy resistance and sensitivity: A comprehensive review

Hua

Deng

et al. 2020

Cancer Science

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MircoRNA (miRNA) are a group of small, non–coding, regulatory RNA with an average length of approximately 22 nucleotides, which mostly modulate gene expression post–transcriptionally through complementary binding to the 3ʹ‐untranslated region (3ʹ‐UTR) of multiple target genes. Emerging evidence has shown that miRNA are frequently dysregulated in a variety of human malignancies. Among them, microRNA‐145 (miR‐145) has been increasingly identified as a critical suppressor of carcinogenesis and therapeutic resistance. Resistance to tumor therapy is a challenge in cancer treatment due to the daunting range of resistance mechanisms. We reviewed the status quo of recent advancements in the knowledge of the functional role of miR‐145 in therapeutic resistance and the tumor microenvironment. It may serve as an innovative biomarker for therapeutic response and cancer prognosis.

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Section: Mir‐145 In Drug Resistancementioning

confidence: 99%

Section: Mir‐145 In Drug Resistancementioning

confidence: 99%

MiR‐145 in cancer therapy resistance and sensitivity: A comprehensive review

Hua

Deng

et al. 2020

Cancer Science

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“…Earlier studies have indicated that Smad2 protein acts as intracellular receptors and plays a critical role in the canonical TGF‐β signaling pathway . At early stages of cancer, TGF‐β exhibits tumor‐suppressive effects by inhibiting the epithelial growth.…”

Section: Discussionmentioning

confidence: 99%

Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR‐155‐5p in EBV‐associated gastric cancer cell lines

Shi

Zhang

et al. 2019

Journal of Medical Virology

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Epstein-Barr virus (EBV) infection is one of the causes of gastric cancer (GC). Besides,previous studies have demonstrated that EBV-encoded latent membrane protein 2A (LMP2A) influences the pathogenesis of EBV-associated gastric cancer (EBVaGC) through regulating several key pathways. In this study, the expression level of Smad2 was observed, which was reduced in EBVaGC cell lines, especially in the presence of LMP2A. Meanwhile, we found that LMP2A promoted the expression of miR-155-5p by activated nuclear factor-κB (NF-κB) signaling. After being treated with NF-κB inhibitor (BAY 11-7082), miR-155-5p sharply decreased. Western blot analysis proved that the overexpression of miR-155-5p could inhibit Smad2. Functional studies showed that the role of miR-155-5p might lead to good prognosis in EBVpositive GC through promoting cell apoptosis and cell cycle arrest, as well as inhibiting tumor proliferation. In addition, p-Smad2 protein was also reduced or induced by overexpression or knockdown, respectively, of miR-155-5p. Immunofluorescence analysis further indicated that LMP2A prevented p-Smad2 from transferring to the nucleus, which played a crucial role in transforming growth factor-β (TGF-β) signaling. In summary, our findings confirmed the relationship between LMP2A and Smad2 and provided a potential regulation of the TGF-β pathway in EBVaGC. K E Y W O R D S LMP2A, miR-155-5p, NF-κB, Smad2, TGF-β signaling pathway 1 | INTRODUCTION Gastric cancer (GC), originating from the gastric mucosa, is a malignant tumor. 1 Evidence shows that GC is caused by multiple factors such as sanitation, food preservation, Helicobacter pylori infection, and Epstein-Barr virus (EBV) infection. 2 EBV was first discovered as an oncogenic virus in humans over 50 years ago. 3 EBV, which adopts both latent and lytic forms of infection, has a high prevalence all over the world, and it is thought that roughly 95% of the world's population presents an asymptomatic life-long infection. 4 EBV is best known as the cause of infectious mononucleosis, a variety of lymphomas, nasopharyngeal carcinoma (NPC), and GC. 4,5 EBV-associated gastric cancer (EBVaGC), detected in approximately 10% of GC cases worldwide, is the monoclonal growth of EBV-infected epithelial cells. 6 EBVaGC belongs to latency type I or II, in which only EBV-encoded RNA, EBV nuclear antigen 1, EBVencoded latent membrane protein 2A (LMP2A) and BART micro-RNAs (miRNAs) are expressed. 7 Plenty of studies have demonstrated that LMP2A might influence genomic features of host DNA, messenger RNA (mRNA), miRNA, and CpG methylation profiles

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“…SMAD4, also called Co-SMAD, is the central mediator of the TGF-β and bone morphogenic protein (BMP) signaling pathways. The N-terminal MH1 is responsible for the DNA binding at level of the specific palindromic sequence GTCTAGAC and contains the NLS, while the C-terminal MH2 domain is important for heteromeric SMAD complexes aggregation, which is necessary for SMAD4 transcriptional activity [161,162]. The linker region between MH1 and MH2 contains the TAD and a nuclear export signal (NES).…”

Section: Smad Family Member 4 (Smad4)mentioning

confidence: 99%

“…SMAD4 inactivation can promote tumor progression and metastasis development in a tumor type-dependent manner. In vivo, SMAD4 deletion contributes to tumorigenesis in head and neck, pancreatic, colon and ovarian human cancers [162,166]. Oppositely, the over-expression of SMAD4 enhances apoptosis and inhibits cancer cell proliferation [162,167].…”

Section: Smad Family Member 4 (Smad4)mentioning

confidence: 99%

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Belluti

Rigillo

Imbriano

2020

Cells

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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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Roles of Smads Family and Alternative Splicing Variants of Smad4 in Different Cancers

Cited by 29 publications

References 94 publications

MiR‐145 in cancer therapy resistance and sensitivity: A comprehensive review

MiR‐145 in cancer therapy resistance and sensitivity: A comprehensive review

Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR‐155‐5p in EBV‐associated gastric cancer cell lines

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

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