MALAT1 modulates alternative splicing by cooperating with the splicing factors PTBP1 and PSF

Science advances

2022 Dec 23

Miao, H;Wu, F;Li, Y;Qin, C;Zhao, Y;Xie, M;Dai, H;Yao, H;Cai, H;Wang, Q;Song, X;Li, L;
PMID: 36563164 | DOI: 10.1126/sciadv.abq7289

Understanding how long noncoding RNAs (lncRNAs) cooperate with splicing factors (SFs) in alternative splicing (AS) control is fundamental to human biology and disease. We show that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-documented AS-implicated lncRNA, regulates AS via two SFs, polypyrimidine tract-binding protein 1 (PTBP1) and PTB-associated SF (PSF). MALAT1 stabilizes the interaction between PTBP1 and PSF, thereby forming a functional module that affects a network of AS events. The MALAT1-stabilized PTBP1/PSF interaction occurs in multiple cellular contexts; however, the functional module, relative to MALAT1 only, has more dominant pathological significance in hepatocellular carcinoma. MALAT1 also stabilizes the PSF interaction with several heterogeneous nuclear ribonucleoparticle proteins other than PTBP1, hinting a broad role in AS control. We present a model in which MALAT1 cooperates with distinct SFs for AS regulation and pose that, relative to analyses exclusively performed for lncRNAs, a comprehensive consideration of lncRNAs and their binding partners may provide more information about their biological functions.

Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis

Cell reports

2022 Oct 18

Brooks, R;Monzy, J;Aaron, B;Zhang, X;Kossenkov, A;Hayden, J;Keeney, F;Speicher, DW;Zhang, L;Dang, CV;
PMID: 36261012 | DOI: 10.1016/j.celrep.2022.111514

We identify ADIRF-AS1 circadian long non-coding RNA (lncRNA). Deletion of ADIRF-AS1 in U2OS cells alters rhythmicity of clock-controlled genes and expression of extracellular matrix genes. ADIRF-AS1 interacts with all components of the PBAF (PBRM1/BRG1) complex in U2OS cells. Because PBRM1 is a tumor suppressor mutated in over 40% of clear cell renal carcinoma (ccRCC) cases, we evaluate ADIRF-AS1 in ccRCC cells. Reducing ADIRF-AS1 expression in ccRCC cells decreases expression of some PBAF-suppressed genes. Expression of these genes is partially rescued by PBRM1 loss, consistent with ADIRF-AS1 acting in part to modulate PBAF. ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant, tumors. Loss of ADIRF-AS1 eliminates in vivo tumorigenesis, partially rescued by concurrent loss of PBRM1 only when co-injected with Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1. Our findings suggest that ADIRF-AS1 functions partly through PBAF to regulate specific genes as a BMAL1-CLOCK-regulated, oncogenic lncRNA.

The Role of Nerve Fibers in the Tumor Immune Microenvironment of Solid Tumors

Advanced biology

2022 Jun 25

Hernandez, S;Serrano, AG;Solis Soto, LM;
PMID: 35751462 | DOI: 10.1002/adbi.202200046

The importance of neurons and nerve fibers in the tumor microenvironment (TME) of solid tumors is now acknowledged after being unexplored for a long time; this is possible due to the development of new technologies that allow in situ characterization of the TME. Recent studies have shown that the density and types of nerves that innervate tumors can predict a patient's clinical outcome and drive several processes of tumor biology. Nowadays, several efforts in cancer research and neuroscience are taking place to elucidate the mechanisms that drive tumor-associated innervation and nerve-tumor and nerve-immune interaction. Assessment of neurons and nerves within the context of the TME can be performed in situ, in tumor tissue, using several pathology-based strategies that utilize histochemical and immunohistochemistry principles, hi-plex technologies, and computational pathology approaches to identify measurable histopathological characteristics of nerves. These features include the number and type of tumor associated nerves, topographical location and microenvironment of neural invasion of malignant cells, and investigation of neuro-related biomarker expression in nerves, tumor cells, and cells of the TME. A deeper understanding of these complex interactions and the impact of nerves in tumor biology will guide the design of better strategies for targeted therapy in clinical trials.

DLEU1 promotes cell survival by preventing DYNLL1 degradation in esophageal squamous cell carcinoma

Journal of translational medicine

2022 May 26

Li, Q;Zhang, Z;Jiang, H;Hou, J;Chai, Y;Nan, H;Li, F;Wang, L;
PMID: 35619131 | DOI: 10.1186/s12967-022-03449-w

Emerging evidence has highlighted the critical roles of long noncoding RNAs (lncRNAs) in tumor development and progression. However, the biological functions and underlying mechanisms of DLEU1 in esophageal squamous cell carcinoma (ESCC) remain unclear.LncRNA expression in ESCC tissues was explored using lncRNA microarray datasets. The functional roles of DLEU1 in ESCC were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down and immunoprecipitation assays were performed to demonstrate the potential mechanisms of DLEU1.In a screen for differentially expressed lncRNAs in ESCC, we determined that DLEU1 was one of the most overexpressed lncRNAs in ESCC tissues and that upregulated DLEU1 expression was associated with a worse prognosis. Functional assays showed that DLEU1 promoted tumor growth by inhibiting cell apoptosis. Mechanistically, DLEU1 could bind and stabilize DYNLL1 by interfering with RNF114-mediated ubiquitination and proteasomal degradation. The DLEU1/DYNLL1 axis subsequently upregulated antiapoptotic BCL2 and promoted cell survival. Furthermore, DLEU1 upregulation was at least partly facilitated by promoter hypomethylation. Notably, targeting DLEU1 sensitized ESCC cells to cisplatin-induced death.Our findings suggest that DLEU1-mediated stabilization of DYNLL1 is critical for cell survival and that the DLEU1/DYNLL1 axis may be a promising therapeutic target for ESCC.

SLCO4A1-AS1 triggers the malignant behaviors of melanoma cells via sponging miR-1306-5p to enhance PCGF2

Experimental dermatology

2022 Apr 15

Wang, K;Li, M;Duan, H;Zhang, T;Xu, C;Yu, F;
PMID: 35427425 | DOI: 10.1111/exd.14577

Melanoma belongs to cutaneous malignancy. Long non-coding RNAs (lncRNAs) have been suggested as crucial effectors in modulating progression of different malignancies, including melanoma. However, novel lncRNA solute carrier organic anion transporter family member 4A1 antisense RNA 1 (SLCO4A1-AS1) was not reported in melanoma. Herein, SLCO4A1-AS1 was detected to be up-regulated in melanoma cell lines compared with human normal melanocytes (HEM-a). Additionally, proliferation, migration and invasion of melanoma cells were weakened but apoptosis was facilitated due to SLCO4A1-AS1 down-regulation. Subsequently, miR-1306-5p was revealed to be sequestered by SLCO4A1-AS1 and down-regulated in melanoma cells. Functional assays further sustained that overexpressed miR-1306-5p had inhibitory influence on proliferation, migration and invasion and promoting influence on apoptosis of melanoma cells. Polycomb group ring finger 2 (PCGF2) was predicted as the downstream of miR-1306-5p, displaying aberrantly high expression in melanoma cell lines. Furthermore, PCGF2 expression was negatively modulated by miR-1306-5p and positively regulated by SLCO4A1-AS1. Finally, rescue assays demonstrated melanoma cell malignant behaviors suppressed by SLCO4A1-AS1 knockdown could be reversed by overexpressed PCGF2. Our study suggested that SLCO4A1-AS1 promoted the melanoma cell malignant behaviors via targeting miR-1306-5p/PCGF2, which might facilitate the discovery of novel biomarkers for melanoma treatment.This article is protected by

Analysis of Non-Relapsed and Relapsed Adult Type Granulosa Cell Tumors Suggests Stable Transcriptomes during Tumor Progression

Current Issues in Molecular Biology

2022 Jan 28

Andersson, N;Haltia, U;Färkkilä, A;Wong, S;Eloranta, K;Wilson, D;Unkila-Kallio, L;Pihlajoki, M;Kyrönlahti, A;Heikinheimo, M;
| DOI: 10.3390/cimb44020048

Adult-type granulosa cell tumor (AGCT) is a rare ovarian malignancy characterized by slow growth and hormonal activity. The prognosis of AGCT is generally favorable, but one-third of patients with low-stage disease experience a late relapse, and over half of them die of AGCT. To identify markers that would distinguish patients at risk for relapse, we performed Lexogen QuantSeq 3′ mRNA sequencing on formalin-fixed paraffin-embedded, archival AGCT tissue samples tested positive for the pathognomonic Forkhead Box L2 (FOXL2) mutation. We compared the transcriptomic profiles of 14 non-relapsed archival primary AGCTs (follow-up time 17-26 years after diagnosis) with 13 relapsed primary AGCTs (follow-up time 1.7-18 years) and eight relapsed tumors (follow-up time 2.8-18.9 years). Non-relapsed and relapsed primary AGCTs had similar transcriptomic profiles. In relapsed tumors three genes were differentially expressed: plasmalemma vesicle associated protein (PLVAP) was upregulated (p = 0.01), whereas argininosuccinate synthase 1 (ASS1) (p = 0.01) and perilipin 4 (PLIN4) (p = 0.02) were downregulated. PLVAP upregulation was validated using tissue microarray RNA in situ hybridization. In our patient cohort with extremely long follow-up, we observed similar gene expression patterns in both primary AGCT groups, suggesting that relapse is not driven by transcriptomic changes. These results reinforce earlier findings that molecular markers do not predict AGCT behavior or risk of relapse.

Giant Cell Tumor of Bone Versus Tenosynovial Giant Cell Tumor- Similarities and Differences

International journal of surgical pathology

2022 Jan 31

Kropivšek, L;Pižem, J;Mavčič, B;
PMID: 35098753 | DOI: 10.1177/10668969221076545

Giant cell tumor of bone (GCTB) and tenosynovial giant cell tumor (TGCT) share misleadingly similar names, soft texture and brown color macroscopically, osteoclast-like multinucleated giant cells microscopically and localisation in the musculoskeletal system. However, these two tumor types are biologically and clinically two distinct entities with different natural courses of progression and considerably different modes of surgical and medical treatment. In this article, we provide a detailed update on the similarities and the differences between both tumor types.GCTB is a locally aggressive osteolytic bone tumor, commonly seen in patients in their third decade of life. It usually occurs as a solitary lesion in the meta-epiphyseal region of long bones. It can be diagnosed using plain radiographic imaging, CT radiography or MRI to estimate the tumor extent, soft tissue and joint involvement. GCTB is usually treated with intralesional excision by curettage. Systemically, it can be treated with bisphosphonates and denosumab or radiotherapy.TGCT is a rare, slowly progressing tumor of synovial tissue, affecting the joint, tendon sheath or bursa, mostly seen in middle-aged patients. TGCT is usually not visible on radiographs and MRI is mostly used to enable assessment of potential bone involvement and distinguishing between two TGCT types. Localised TGCT is mostly treated with marginal surgical resection, while diffuse TGCT is optimally treated with total synovectomy and is more difficult to remove. Additionally, radiotherapy, intraarticular injection of radioactive isotopes, anti-TNF-α antibodies and targeted medications may be used.

LncRNA IFITM4P promotes immune escape by up-regulating PD-L1 via dual mechanism in oral carcinogenesis

Molecular therapy : the journal of the American Society of Gene Therapy

2022 Jan 17

Shi, L;Yang, Y;Li, M;Li, C;Zhou, Z;Tang, G;Wu, L;Yao, Y;Shen, X;Hou, Z;Jia, H;
PMID: 35051616 | DOI: 10.1016/j.ymthe.2022.01.003

Oral squamous cell carcinoma (OSCC), which is typically preceded by oral leukoplakia (OL), is a common malignancy with poor prognosis. However, the signaling molecules governing this progression remain to be defined. Based on microarray analysis of genes expressed in OL and OSCC samples, we discovered that the long non-coding RNA IFITM4P was highly expressed in OSCC, and ectopic expression or knockdown of IFITM4P resulted in increased or decreased cell proliferation in vitro and in xenografted tumors, respectively. Mechanistically, in the cytoplasm IFITM4P acted as a scaffold to facilitate recruiting SASH1 to bind and phosphorylate TAK1 (Thr187), and in turn to increase the phosphorylation of nuclear factor κB (Ser536) and concomitant induction of PD-L1 expression, resulting in activation of an immunosuppressive program that allows OL cells to escape anti-cancer immunity in cytoplasm. In nucleus, IFITM4P reduced Pten transcription by enhancing the binding of KDM5A to the Pten promoter, thereby upregulating PD-L1 in OL cells. Moreover, mice bearing tumors with high IFITM4P expression had notable therapeutic sensitivity to PD-1 monoclonal antibody (mAb) treatment. Collectively, these data demonstrate that IFITM4P may serve as a new therapeutic target in blockage of oral carcinogenesis, and PD-1 mAb can be an effective reagent to treat OSCC.

LINC00885 promotes cervical cancer progression through sponging miR-3150b-3p and upregulating BAZ2A

Biology direct

2022 Jan 10

Liu, Y;Chen, J;Zhou, L;Yin, C;
PMID: 35012615 | DOI: 10.1186/s13062-021-00314-6

Cervical cancer (CC) is one of the most common malignancies affecting female worldwide. Long non-coding RNAs (lncRNAs) are increasingly indicated as crucial participants and promising therapeutic targets in human cancers. The main objective of this study was to explore the functions and mechanism of LINC00885 in CC.RT-qPCR and western blot were used to detect RNA and protein levels. Functional and mechanism assays were respectively done for the analysis of cell behaviors and molecular interplays.Long intergenic non-coding RNA 885 (LINC00885) was discovered to be upregulated in CC tissues and cell lines through bioinformatics analysis and RT-qPCR. Overexpression of LINC00885 promoted proliferation and inhibited apoptosis, whereas its silence exerted opposite effects. The cytoplasmic localization of LINC00885 was ascertained and furthermore, LINC00885 competitively bound with miR-3150b-3p to upregulate BAZ2A expression in CC cells. Rescue assays confirmed that LINC00885 regulated CC proliferation and apoptosis through miR-3150b-3p/BAZ2A axis. Finally, we confirmed that LINC00885 aggravated tumor growth through animal experiments.LINC00885 exerted oncogenic function in CC via regulating miR-3150b-3p/BAZ2A axis. These findings suggested LINC00885 might serve as a potential promising therapeutic target for CC patients.

SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback

Cancer letters

2021 Dec 25

Liu, S;Bu, X;Kan, A;Luo, L;Xu, Y;Chen, H;Lin, X;Lai, Z;Wen, D;Huang, L;Shi, M;
PMID: 34958891 | DOI: 10.1016/j.canlet.2021.12.026

Oxaliplatin-based chemotherapy is widely used to treat advanced hepatocellular carcinoma (HCC), but many patients develop drug resistance that leads to tumor recurrence. Cancer stem cells (CSCs) are known to contribute to chemoresistance, the underlying mechanism, however, remains largely unknown. In this study, we discovered a specificity protein 1 (SP1)-induced long noncoding RNA--DPPA2 upstream binding RNA (DUBR) and its high expression in HCC tissues and liver CSCs. DUBR was associated with HCC progression and poor chemotherapy response. Moreover, DUBR facilitated the stemness and oxaliplatin resistance of HCC in vitro and in vivo. Mechanistically, DUBR upregulated cancerous inhibitor of protein phosphatase 2A (CIP2A) expression through E2F1-mediated transcription regulation. DUBR also exerted function by binding microRNA (miR)-520d-5p as a competing endogenous RNA to upregulate CIP2A at mRNA level. CIP2A, in turn, stabilized E2F1 protein and activated the Notch1 signaling pathway, thereby increasing the stemness feature of HCC and leading to chemoresistance. In conclusion, we identified SP1/DUBR/E2F1-CIP2A as a critical axis to activate the Notch1 signaling pathway and promote stemness and chemoresistance of HCC. Therefore, DUBR could be a potential target in HCC treatment.

MALAT1 Inhibits Proliferation of HPV16-Positive Cervical Cancer by Sponging miR-485-5p to Promote Expression of MAT2A

DNA and cell biology

2021 Oct 04

Tie, W;Ge, F;
PMID: 34610246 | DOI: 10.1089/dna.2020.6205

Cervical cancer is the leading cause of morbidity and mortality in women throughout the world, human papillomavirus 16 (HPV16) is the main type of HPV causing invasive cervical cancer. However, the underlying mechanism of the high carcinogenicity of HPV16 remains unclear. In the current study, we documented that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA, is upregulated in HPV16-positive cervical cancer tissue and cell lines. The results of immunohistochemistry and immunofluorescence showed that MALAT1 was mainly localized in the cytoplasm. To clarify the biological functions of MALAT1 in cervical cancer cells, we performed gain- and loss-of-function experiments to explore the underlying molecular mechanism. Functionally, the proliferation of cervical cancer was detected by Cell Counting Kit-8 (CCK-8) and colony formation assay in MALAT1 overexpression or knockdown cells, our data showed that MALAT1 promotes the proliferation of cervical cancer cells. Mechanistically, our results suggested that MALAT1 upregulates Methionine adenosyltransferase 2A (MAT2A) by sponging miR-485-5p. Moreover, the gain-of-function assay validated the function of MAT2A in HPV16-positive cervical cancer proliferation. Taken together, our results demonstrated that MALAT1 acts as a competitive endogenous RNA (ceRNA) to regulate MAT2A by sponging miR-485-5p in HPV16-positive cervical cancer, suggesting that MALAT1 may act as a potential therapeutic target for HPV16-positive cervical cancer.

LncRNA PCIR Is an Oncogenic Driver via Strengthen the Binding of TAB3 and PABPC4 in Triple Negative Breast Cancer

Frontiers in oncology

2021 May 03

Guo, W;Li, J;Huang, H;Fu, F;Lin, Y;Wang, C;
PMID: 34012913 | DOI: 10.3389/fonc.2021.630300

Long non-coding RNAs (LncRNA) as the key regulators in all stages of tumorigenesis and metastasis. However, the underlying mechanisms are largely unknown. Here, we report a lncRNA RP11-214F16.8, which renamed Lnc-PCIR, is upregulated and higher RNA level of Lnc-PCIR was positively correlated to the poor survival of patients with triple negative breast cancer (TNBC) tissues. Lnc-PCIR overexpression significantly promoted cell proliferation, migration, and invasion in vitro and in vivo. RNA pulldown, RNA immunoprecipitation (RIP) and RNA transcriptome sequencing technology (RNA-seq) was performed to identify the associated proteins and related signaling pathways. Mechanistically, higher Lnc-PCIR level of blocks PABPC4 proteasome-dependent ubiquitination degradation; stable and highly expressed PABPC4 can further increase the stability of TAB3 mRNA, meanwhile, overexpression of Lnc-PCIR can disrupt the binding status of TAB3 and TAB2 which lead to activate the TNF-α/NF-κB pathway in TNBC cells. Our findings suggest that Lnc-PCIR promotes tumor growth and metastasis via up-regulating the mRNA/protein level of TAB3 and PABPC4, activating TNF-α/NF-κB signaling pathway in TNBC.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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