A Wnt-Induced lncRNA-DGCR5 Splicing Switch Drives Tumor-Promoting Inflammation in Esophageal Squamous Cell Carcinoma

SSRN Electronic Journal

2022 Dec 02

Li, Y;Chen, B;Jiang, X;Li, Y;Huang, S;Xiao, Y;Shi, D;Huang, X;He, L;Chen, X;Ouyang, Y;Li, J;Song, L;Lin, C;
| DOI: 10.2139/ssrn.4287908

Alternative splicing (AS) is a critical mechanism for the aberrant biogenesis of long non-coding RNA (lncRNA). Although the role of Wnt signaling in AS has been implicated, it remains unclear how it mediates lncRNA splicing during cancer progression. Herein, we identify that Wnt3a induces a splicing switch of lncRNA-DGCR5 to generate a short variant (DGCR5-S) which correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). Upon Wnt3a stimulation, activated nuclear β-Catenin acts as a cofactor of FUS to facilitate the spliceosome assembly and the splicing generation of DGCR5-S. DGCR5-S inhibits TTP’s anti-inflammatory activity by protecting it from PP2A-mediated dephosphorylation, thus fostering tumor-promoting inflammation. Importantly, synthetic splice-switching oligonucleotides (SSO) disrupt the splicing switch of DGCR5 and potently suppress tumor growth of Patient-derived xenografts (PDXs). These findings uncover the mechanism for Wnt signaling in lncRNA splicing and suggest that the DGCR5 splicing switch may be a targetable vulnerability in ESCC.

LncRNA LITATS1 suppresses TGF-β-induced EMT and cancer cell plasticity by potentiating TβRI degradation

The EMBO journal

2023 Mar 30

Fan, C;Wang, Q;Kuipers, TB;Cats, D;Iyengar, PV;Hagenaars, SC;Mesker, WE;Devilee, P;Tollenaar, RAEM;Mei, H;Ten Dijke, P;
PMID: 36994542 | DOI: 10.15252/embj.2022112806

Epithelial cells acquire mesenchymal phenotypes through epithelial-mesenchymal transition (EMT) during cancer progression. However, how epithelial cells retain their epithelial traits and prevent malignant transformation is not well understood. Here, we report that the long noncoding RNA LITATS1 (LINC01137, ZC3H12A-DT) is an epithelial gatekeeper in normal epithelial cells and inhibits EMT in breast and non-small cell lung cancer cells. Transcriptome analysis identified LITATS1 as a TGF-β target gene. LITATS1 expression is reduced in lung adenocarcinoma tissues compared with adjacent normal tissues and correlates with a favorable prognosis in breast and non-small cell lung cancer patients. LITATS1 depletion promotes TGF-β-induced EMT, migration, and extravasation in cancer cells. Unbiased pathway analysis demonstrated that LITATS1 knockdown potently and selectively potentiates TGF-β/SMAD signaling. Mechanistically, LITATS1 enhances the polyubiquitination and proteasomal degradation of TGF-β type I receptor (TβRI). LITATS1 interacts with TβRI and the E3 ligase SMURF2, promoting the cytoplasmic retention of SMURF2. Our findings highlight a protective function of LITATS1 in epithelial integrity maintenance through the attenuation of TGF-β/SMAD signaling and EMT.

LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer

Cell death and differentiation

2023 Apr 08

Shi, L;Duan, R;Sun, Z;Jia, Q;Wu, W;Wang, F;Liu, J;Zhang, H;Xue, X;
PMID: 37031273 | DOI: 10.1038/s41418-023-01157-6

Dysregulation of long noncoding RNAs (lncRNAs) has been associated with the development and progression of many human cancers. Lactate dehydrogenase A (LDHA) enzymatic activity is also crucial for cancer development, including the development of papillary thyroid cancer (PTC). However, whether specific lncRNAs can regulate LDHA activity during cancer progression remains unclear. Through screening, we identified an LDHA-interacting lncRNA, GLTC, which is required for the increased aerobic glycolysis and cell viability in PTC. GLTC was significantly upregulated in PTC tissues compared with nontumour thyroid tissues. High expression of GLTC was correlated with more extensive distant metastasis, a larger tumour size, and poorer prognosis. Mass spectrometry revealed that GLTC, as a binding partner of LDHA, promotes the succinylation of LDHA at lysine 155 (K155) via competitive inhibition of the interaction between SIRT5 and LDHA, thereby promoting LDHA enzymatic activity. Overexpression of the succinylation mimetic LDHAK155E mutant restored glycolytic metabolism and cell viability in cells in which metabolic reprogramming and cell viability were ceased due to GLTC depletion. Interestingly, GLTC inhibition abrogated the effects of K155-succinylated LDHA on radioiodine (RAI) resistance in vitro and in vivo. Taken together, our results indicate that GLTC plays an oncogenic role and is an attractive target for RAI sensitisation in PTC treatment.

Anti-HERV-K Drugs and Vaccines, Possible Therapies against Tumors

Vaccines

2023 Mar 28

Hosseiniporgham, S;Sechi, LA;
PMID: 37112663 | DOI: 10.3390/vaccines11040751

The footprint of human endogenous retroviruses (HERV), specifically HERV-K, has been found in malignancies, such as melanoma, teratocarcinoma, osteosarcoma, breast cancer, lymphoma, and ovary and prostate cancers. HERV-K is characterized as the most biologically active HERV due to possession of open reading frames (ORF) for all Gag, Pol, and Env genes, which enables it to be more infective and obstructive towards specific cell lines and other exogenous viruses, respectively. Some factors might contribute to carcinogenicity and at least one of them has been recognized in various tumors, including overexpression/methylation of long interspersed nuclear element 1 (LINE-1), HERV-K Gag, and Env genes themselves plus their transcripts and protein products, and HERV-K reverse transcriptase (RT). Therapies effective for HERV-K-associated tumors mostly target invasive autoimmune responses or growth of tumors through suppression of HERV-K Gag or Env protein and RT. To design new therapeutic options, more studies are needed to better understand whether HERV-K and its products (Gag/Env transcripts and HERV-K proteins/RT) are the initiators of tumor formation or just the disorder's developers. Accordingly, this review aims to present evidence that highlights the association between HERV-K and tumorigenicity and introduces some of the available or potential therapies against HERV-K-induced tumors.

LncRNA CACClnc promotes chemoresistance of colorectal cancer by modulating alternative splicing of RAD51

Oncogene

2023 Mar 11

Zhang, X;Ma, D;Xuan, B;Shi, D;He, J;Yu, M;Xiong, H;Ma, Y;Shen, C;Guo, F;Cao, Y;Yan, Y;Gao, Z;Tong, T;Zhu, X;Fang, JY;Chen, H;Hong, J;
PMID: 36906654 | DOI: 10.1038/s41388-023-02657-y

Long non-coding RNAs (lncRNAs) play important roles in carcinogenesis. However, the effect of lncRNA on chemoresistance and RNA alternative splicing remains largely unknown. In this study, we identified a novel lncRNA, CACClnc, which was upregulated and associated with chemoresistance and poor prognosis in colorectal cancer (CRC). CACClnc promoted CRC resistance to chemotherapy via promoting DNA repair and enhancing homologous recombination in vitro and in vivo. Mechanistically, CACClnc specifically bound to Y-box binding protein 1 (YB1, a splicing factor) and U2AF65 (a subunit of U2AF splicing factor), promoting the interaction between YB1 and U2AF65, and then modulated alternative splicing (AS) of RAD51 mRNA, and consequently altered CRC cell biology. In addition, expression of exosomal CACClnc in peripheral plasma of CRC patients can effectively predict the chemotherapy effect of patients before treatment. Thus, measuring and targeting CACClnc and its associated pathway could yield valuable insight into clinical management and might ameliorate CRC patients' outcomes.

Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

Science advances

2023 Feb 03

Sun, C;Ye, Y;Tan, Z;Liu, Y;Li, Y;Hu, W;Liang, K;Egranov, SD;Huang, LA;Zhang, Z;Zhang, Y;Yao, J;Nguyen, TK;Zhao, Z;Wu, A;Marks, JR;Caudle, AS;Sahin, AA;Gao, J;Gammon, ST;Piwnica-Worms, D;Hu, J;Chiao, PJ;Yu, D;Hung, MC;Curran, MA;Calin, GA;Ying, H;Han, L;Lin, C;Yang, L;
PMID: 36724291 | DOI: 10.1126/sciadv.add6995

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1

Proceedings of the National Academy of Sciences of the United States of America

2023 Feb 21

Zhang, Z;Lu, YX;Liu, F;Sang, L;Shi, C;Xie, S;Bian, W;Yang, JC;Yang, Z;Qu, L;Chen, SY;Li, J;Yang, L;Yan, Q;Wang, W;Fu, P;Shao, J;Li, X;Lin, A;
PMID: 36795754 | DOI: 10.1073/pnas.2206694120

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

LncRNA MALAT1 promotes growth and metastasis of head and neck squamous cell carcinoma by repressing VHL through a non-canonical function of EZH2

Cell death & disease

2023 Feb 22

Duan, Y;Yue, K;Ye, B;Chen, P;Zhang, J;He, Q;Wu, Y;Lai, Q;Li, H;Wu, Y;Jing, C;Wang, X;
PMID: 36813772 | DOI: 10.1038/s41419-023-05667-6

Long non-coding RNAs (LncRNAs) are implicated in malignant progression of human cancers. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well-known lncRNA, has been reported to play crucial roles in multiple malignancies including head and neck squamous cell carcinoma (HNSCC). However, the underlying mechanisms of MALAT1 in HNSCC progression remain to be further investigated. Here, we elucidated that compared with normal squamous epithelium, MALAT1 was notably upregulated in HNSCC tissues, especially in which was poorly differentiated or with lymph nodes metastasis. Moreover, elevated MALAT1 predicted unfavorable prognosis of HNSCC patients. The results of in vitro and in vivo assays showed that targeting MALAT1 could significantly weaken the capacities of proliferation and metastasis in HNSCC. Mechanistically, MALAT1 inhibited von Hippel-Lindau tumor suppressor (VHL) by activating EZH2/STAT3/Akt axis, then promoted the stabilization and activation of β-catenin and NF-κB which could play crucial roles in HNSCC growth and metastasis. In conclusion, our findings reveal a novel mechanism for malignant progression of HNSCC and suggest that MALAT1 might be a promising therapeutic target for HNSCC treatment.

Causal Link of Human Papillomavirus in Barrett Esophagus and Adenocarcinoma: Are We There Yet?

Cancers

2023 Jan 31

Rajendra, S;Sharma, P;
PMID: 36765833 | DOI: 10.3390/cancers15030873

Esophageal cancer is a relatively common malignancy worldwide with a high mortality (5-year survival of <15%). Despite screening, surveillance, improved imaging and treatment, the exponential rise in OAC continues. The strongest risk factors for OAC are chronic heartburn and metaplastic transformation of the lower third of the esophagus (Barrett's esophagus). The risk profile includes Caucasian race, male gender older age, obesity and smoking. Although the tumor risk in BO has been progressively revised downwards, the exponential rise in OAC remains unchecked. This paradox points to an unidentified missing link. Relatively recently, we provided the world's initial data for a strong association of biologically relevant hr-HPV with BD and OAC. Since then, systematic reviews and meta-analysis have documented HPV DNA prevalence rates in OAC of between 13 to 35%. In this review, we provide some evidence for a probable causal relationship between hr-HPV and OAC. This is challenging given the multifactorial etiology and long latency. Increasingly, high-risk HPV (hr-HPV) is regarded as a risk factor for OAC. This discovery will aid identification of a sub-group of high-risk progressors to esophageal cancer by surveillance and the development of effective preventive strategies including vaccination.

Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System

International journal of tryptophan research : IJTR

2023 Feb 09

Abu Hejleh, AP;Huck, K;Jähne, K;Tan, CL;Lanz, TV;Epping, L;Sonner, JK;Meuth, SG;Henneberg, A;Opitz, CA;Herold-Mende, C;Sahm, F;Platten, M;Sahm, K;
PMID: 36798537 | DOI: 10.1177/11786469231153111

The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11+ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.

Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker

bioRxiv : the preprint server for biology

2023 Jan 25

Taylor, MS;Wu, C;Fridy, PC;Senussi, Y;Cheng, WC;Heaps, J;Mori, K;Cohen, L;Molloy, KR;Chait, BT;Goggins, M;Bhan, I;Franses, JW;Yang, X;Taplin, ME;Wang, X;Christiani, DC;Johnson, BE;Meyerson, M;Uppaluri, R;Egloff, AM;Denault, EN;Spring, LM;Wang, TL;Shih, IM;Jung, E;Arora, KS;Zukerberg, LR;Yilmaz, OH;Chi, G;Norden, BL;Song, Y;Nieman, L;Parikh, AR;Strickland, M;Mustelin, T;Eng, G;Yilmaz, ÖH;Matulonis, UA;Skates, SJ;Rueda, BR;Drapkin, R;Klempner, SJ;Deshpande, V;Ting, DT;Rout, MP;LaCava, J;Walt, DR;Burns, KH;
PMID: 36747644 | DOI: 10.1101/2023.01.25.525462

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1, L1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible detectable expression in corresponding normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore the potential of ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10 -17 M) ORF1p concentrations in patient plasma samples across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, and provides early therapeutic response monitoring in gastric and esophageal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring.

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia

bioRxiv : the preprint server for biology

2023 Jan 14

Sun, Q;van de Lisdonk, D;Ferrer, M;Gegenhuber, B;Wu, M;Tollkuhn, J;Janowitz, T;Li, B;
PMID: 36711916 | DOI: 10.1101/2023.01.12.523716

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia 1-15 . It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia 16-20 . However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-6 1-5,15,18,21-23 , leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra , the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.

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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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