Long non-coding RNAs (lncRNAs) function as key molecules in cancer progression. The lncRNA CYTOR plays oncogenic roles in multiple types of cancer, yet the detailed molecular mechanisms of those ...roles remain unknown. The aim of this study was to investigate the clinical significance, biological function and interacting partners of CYTOR in colorectal cancer (CRC).
A systematic and comprehensive analysis of CYTOR expression was performed in 138 CRC samples and in the TCGA and GEO databases. Biological function was investigated through knockdown and overexpression of CYTOR in vitro and in vivo. In addition, its protein binding partner was identified and validated using ChIRP-MS and RNA immunoprecipitation assays. Their key interaction sites on CYTOR were verified by CRISPR/Cas9 and a series of mutant constructs. Furthermore, the downstream targets of CYTOR were confirmed via immunoblotting and luciferase reporter assays.
CYTOR was significantly up-regulated in CRC samples and associated with poor prognosis, promoting proliferation and metastasis in vitro and in vivo. NCL and Sam68 could recognize their specific motifs and directly bind to EXON1 of CYTOR. Moreover, EXON1 was the key functional site mediating the interaction of CYTOR with NCL and Sam68. NCL and Sam68 functioned as oncogenes to promote CRC progression. Furthermore, we confirmed that the heterotrimeric complex of CYTOR, NCL and Sam68 activated the NF-κB pathway and EMT to contribute to CRC progression.
CYTOR plays important roles in CRC progression by interacting with NCL and Sam68 and may serve as a prognostic biomarker and/or an effective target for CRC therapies.
miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3'-untranslated regions of the downstream gene mRNAs to ...repress mRNA expression. Mounting investigations forcefully document that not only does miR‑22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR‑22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR‑22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR‑22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis.
Enzyme-linked immunosorbent assay (ELISA) is one of the most common techniques in biomedical detection; however, the poor sensitivity in early diagnosis for some diseases seriously limits its ...application. In this work, we developed an ultrasensitive ELISA system that is based on horseradish peroxidase (HRP)-loaded dendritic mesoporous silica nanoparticles (DMSN) modified with poly(amino acid) multilayers (defined as DSHP). A large amount of HRP adsorption was achieved in center-radial mesoporous channels of DMSN because of the high specific surface area and large pore size, leading to significant signal amplification. Additionally, DSHP could not only effectively maintain HRP activity for at least 10 days but also provide preferable protection for HRP activity even at high temperatures or a wide pH range. Moreover, the DSHP system exhibited admirable signal amplification performance with a limit of detection of 0.667 fM and a wide detectable range from 6.67 × 10–4 to 6.67 × 105 pM, whose sensitivity was 104 times higher than that of the conventional ELISA. We believe that the DSHP will offer a new strategy for signal amplification of the ELISA system in clinical diagnosis.
UTP23 (UTP23 small subunit processome component) plays a pivotal role in the intricate processing and maturation of the small subunit of ribosomes within the nucleolus. In cases of nucleolar stress, ...such as those observed in certain tumor cells, the aberrant nucleolar organization and structure can lead to the translocation of nucleolar proteins into the nucleus or cytoplasm, consequently impacting the physiological processes of the tumor cells through non-ribosome-related functions. Our investigation revealed altered localization of UTP23 protein in colorectal cancer clinical tissue samples. Upon analyzing UTP23 expression and its correlation with patient prognosis in a cohort of 143 colorectal cancer patients, the result suggested that high cytoplasmic expression pattern of UTP23 was occured in early-stage metastasis-free colorectal cancer and was significantly associated with poor prognosis. Furthermore, we demonstrated that cytoplasmic expression of UTP23 significantly promoted the metastatic and invasive capabilities of colorectal cancer cells, which was not showed in the nucleollcalised UTP23. Intriguingly, mass spectrometry result suggested that KRT5 bind to UTP23 and showed a regulatory influence on UTP23 metastatic potential in colorectal cancer cells. Conclusively, our study demonstrated that the localization of UTP23 play a key role in colorectal cancer metastatic progression, which may serve as a novel prognostic indicator.
Highlights • We summarize the feedback loop mechanisms regulating EMT between miRNAs and EMT-related molecules. • We summarize different miRNAs function as oncogenes or tumor suppressor to inhibit or ...promote EMT. • We summarize one miRNA has dual effects on EMT in the different human cancers. • We summarize miRNAs can inhibit or promote EMT through regulating methylation or hydroxymethylation. • We summarize the mechanism of miRNAs controlling EMT to alter tumor chemoradiosensitivity or chemoradioresistance.
Epithelioid and spindle rhabdomyosarcoma (ES-RMS) with TFCP2 rearrangement is a recently discovered rare variant of rhabdomyosarcoma composed of epithelioid and spindle cells, because it shows ...extraordinarily adverse prognosis and is easily misdiagnosed as other epithelioid or spindle cell tumors.
A rare case of ES-RMS with TFCP2 rearrangement was presented and English literatures in Pubmed online up to 01 July 2022 were gathered by two authors for a systematic review according to the inclusion and exclusion criteria.
We report a case of ES-RMS in an early 30s-years-old female, the neoplastic cells are remarkably immunoreactive with CK(AE1/AE3), and partially with ALK protein. Unexpectedly, the tumor shows TFCP2 rearrangement with coexistence of increased copy numbers of EWSR1 and ROS1 gene and MET gene mutation. Besides, Next-generation sequencing for genetic mutational profiling revealed frequent MET exon14 mutations in chromosome 7, most of which are C > T nonsynonymous SNV, and exon42 of ROS1 in chromosome 6 showed frequent G > T mutation up to 57.54%. In addition, neither MyoD1 mutation nor gene fusions were detected. Moreover, the patient shows high tumor mutational burden (TMB) up to 14.11 counts/Mb. Finally, as many cases of ES-RMS including our case had local progression or metastasis, we find, similar to epithelioid rhabdomyosarcoma (median survival time is 10 month), ES-RMS shows a more aggressive behavior and adverse prognosis (median survival time is 17 month) than spindle cell/sclerosing rhabdomyosarcoma (median survival time is 65 month) according previous studies.
ES-RMS with TFCP2 rearrangement is a rare malignant tumor and easily confused with other epithelioid or spindle cell tumors, it may harbor additional gene alteration in addition to TFCP2 rearrangement, such as MET mutation, increased copy numbers of EWSR1 and ROS1 gene, high TMB. Most importantly, it may show very poor outcome with extensive metastasis.
Epigenetics is the study of inherited changes in phenotype or gene expression that do not alter DNA sequence. Recently, scientists have focused their attention on 5-hydroxymethylcytosine (5hmC), a ...newly discovered epigenetic marker, also known as sixth DNA base of the genome. In mammals, this novel epigenetic marker is derived from 5-methylcytosine (5mC) in a process catalyzed by ten-eleven translocation (TET) enzymes. Although 5hmC has only been subjected to study for a short while, a great deal of data has been accumulated regarding its generation, distribution, demethylation, function, and disease implications. All this information suggested that 5hmC acts not only as an intermediate in the DNA demethylation process but also as an independent epigenetic marker, playing an important role in the regulation of gene expression. This review focuses on recent progress in the study of the relationship between 5hmC and human diseases, such as cancer and Rett syndrome (RTT).
As the fifth most common cancer in the world, gastric cancer (GC) ranks as the third major cause of cancer-related death globally. Although surgical resection and chemotherapy still remains the ...mainstay of potentially curative treatment for GC, chemotherapy resistance and adverse side effects limit their clinical applications. Thus, further investigation of the mechanisms of carcinogenesis in GC and discovery of novel biomarkers is of great concern. We herein report that the elevated expression of GPR137 is correlated with GC. Overexpression of GPR137 potentiates human gastric cancer AGS cell malignancy, including proliferation, migration, invasion, colony formation and xenograft growth in nude mice in vivo, whereas knockout of GPR137 by CRISPR/Cas9 gene editing exerts the opposite effects. Mechanistically, GPR137 could bind to MST, the upstream kinases in Hippo pathway, which disrupts the association of MST with LATS, subsequently activating the transcriptional co-activators, YAP and TAZ, and thereby triggering the target transcription and the alterations in GC cell biological actions consequently. Therefore, our findings may provide with the evidence of developing a potentially novel treatment method with specific target for GC.
Although anti–programmed death‐1 (PD‐1)/programmed death ligand 1 (PD‐L1) immunotherapy has achieved great success in some cancers, most colorectal cancer (CRC) patients remain unresponsive. ...Therefore, further clarification of the underlying mechanisms is needed to improve the therapy. In this study, we explored the distinct functions of different PD‐L1 alternative splicing isoforms in CRC. We investigated the biological functions in PD‐L1 knocked down/knockout cells, which were verified through overexpression of PD‐L1 isoforms a, b, and c. The roles of PD‐L1 isoforms in immune surveillance resistance was also analyzed. Meanwhile, we performed RNA‐seq to screen the downstream molecules regulated by PD‐L1 isoforms. Finally, we detected PD‐L1 and PD‐L1 isoforms levels in a cohort of serum samples, two cohorts of CRC tissue samples, and analyzed the correlation of PD‐L1 isoforms with PD‐1 blockade therapy response in two clinical CRC cases. The results indicated that PD‐L1 knockout inhibited proliferation, migration, and invasion, and isoform b exerted a more significant inhibitory effect on T cells than the other two isoforms. Moreover, isoform c could promote CRC progression through regulating epithelial‐mesenchymal transition. Clinical data showed that CRC patients with positive PD‐L1 expression were associated with poorer overall survival. High serum PD‐L1 level was associated with poor prognosis. The level of isoform b or c was negatively associated with prognosis, and a higher level of isoform b was associated with a good response to anti–PD‐1 therapy. In conclusion, isoform b should be considered as a biomarker for clinical responsiveness to anti–PD‐1/PD‐L1 immunotherapy; isoform c had a prometastatic role and is a new potential target for CRC therapy.
In this report, we found that PD‐L1 isoform b could exert a more significant inhibitory effect on T cells than the other two isoforms, and it should be considered as a biomarker of clinical response to immune checkpoint blockade therapy. PD‐L1 isoform c is a prometastatic gene that promotes colorectal cancer progression through regulating epithelial‐mesenchymal transition. It should be considered as a potential prognostic biomarker and an effective target for tumor therapy. Moreover, these findings raise the possibility that PD‐L1 alternative splicing might become a novel target for colorectal cancer immunotherapy.
Intrahepatic cholangiocarcinoma (CCA), always diagnosed at an advanced stage in recent years, is of high aggression and poor prognosis. There is no standard treatment beyond first-line chemotherapy ...and no molecular-targeted agents or immune checkpoint inhibitors approved for advanced intrahepatic CCA. Hence, we firstly report an original therapeutic strategy for a 60-year-old patient diagnosed with intrahepatic CCA categorized as Stage IIIB (T3N1M0) by the American Joint Committee on Cancer staging system. After histopathological examination and next-generation sequencing, the patient was treated with four courses of novel systemic sequential therapy (intravenous gemcitabine 1,000 mg/m
2
and cisplatin 25 mg/m
2
on days 1 and 8; oral lenvatinib 8 mg/day from days 1 to 21; intravenous tislelizumab 200 mg on day 15). Then, the patient achieved partial response and was operated on right hemihepatectomy, cholecystectomy, and abdominal lymph node dissection. Without any perioperative complications, the patient was discharged from our hospital in perfect condition. Thereafter, the patient continued to use this new regimen 1 month after surgery for adjuvant therapy and was confirmed without recurrence when we followed up. In a word, we found an effective therapeutic regimen for preoperative advanced intrahepatic CCA conversion therapy, which may become a new approach in cancer treatment in the future.
PDF
