Development Of Multiple Cancers Research Articles

Overexpression of SOCS2 Inhibits EMT and M2 Macrophage Polarization in Cervical Cancer via IL-6/JAK2/STAT3 Pathway.

SOCS2 is a member of the suppressor of cytokine signaling (SOCS) protein family associated with the occurrence and development of multiple cancers. This study revealed the expression and molecular mechanisms of SOCS2 in cervical cancer. In this study, RT-qPCR, Western Blot, and immunohistochemistry were used to detect the expression level of SOCS2 in cervical cancer tissues and tumor cells. We overexpressed SOCS2 in SiHa cells via lentivirus. In-vitro experiments were used to investigate the changes in cervical cancer cell proliferation, migration, and invasion ability before and after SOCS2 overexpression. Western Blot was used to detect the expression of IL-6/JAK2/STAT3 pathway and EMTrelated proteins. M0 macrophages were co-cultured with the tumor-conditioned medium. The effect of SOCS2 on macrophage polarization was examined by RT-qPCR. SOCS2 expression level was significantly downregulated in cervical cancer tissues. SOCS2 was negatively correlated with CD163+M2 macrophages. Overexpression of SOCS2 inhibited the proliferation, migration, and invasion of cervical cancer cells. The expressions of Twist- 2, N-cadherin, and Vimentin were decreased, while the expression of E-cadherin was increased. Moreover, the expression of IL-6, p-JAK2, and p-STAT3 were decreased. After the addition of RhIL-6, the expression of E-cadherin protein in the LV-SOCS2 group was reversed. CM in the LV-SOCS2 group inhibited the polarization of M2 macrophages. SOCS2 acts as a novel biological target and suppressor of cervical cancer through IL- 6/JAK2/STAT3 pathway.

Structural determinants for membrane binding of the EGFR juxtamembrane domain.

Overactivation of the epidermal growth factor receptor (EGFR) is critical for the development of multiple cancers. Previous studies have shown that the cell membrane is a key regulator of EGFR kinase activity through its interaction with the EGFR juxtamembrane domain (JM). However, the lipid recognition specificity of EGFR-JM and its interaction details remain unclear. Using lipid strip and liposome pulldown assays, we showed that EGFR-JM could specifically interact with PI(4,5)P2-or phosphatidylserine-containing membranes. We further characterized the JM-membrane interaction using NMR-titration-based chemical shift perturbation and paramagnetic relaxation enhancement analyses, and found that residues I649 - L659 comprised the membrane-binding site. Furthermore, the membrane-binding region contains the predicted dimerization motif of JM, 655LRRLL659, suggesting that membrane binding may affect JM dimerization and, therefore, regulate kinase activation.

PGD2/PTGDR2 Signal Affects the Viability, Invasion, Apoptosis, and Stemness of Gastric Cancer Stem Cells and Prevents the Progression of Gastric Cancer.

Prostaglandin D2 (PGD2) has been shown to restrict the occurrence and development of multiple cancers; nevertheless, its underlying molecular mechanism has not been fully elucidated. The present study investigated the effect of PGD2 on the biological function of the enriched gastric cancer stem cells (GCSCs), as well as its underlying molecular mechanism, to provide a theoretical basis and potential therapeutic drugs for gastric cancer (GC) treatment. The plasma PGD2 levels were detected by Enzyme-linked immunosorbent assay (ELISA). Silencing of lipocalin prostaglandin D synthetases (L-PTGDS) and prostaglandin D2 receptor 2 (PTGDR2) was carried out in GCSCs from SGC-7901 and HGC-27 cell lines. Cell Counting Kit-8, transwell, flow cytometry, and western blotting assays were used to determine cell viability, invasion, apoptosis, and stemness of GCSCs. In vivo xenograft models were used to assess tumor growth. Clinically, it was found that the plasma PGD2 level decreased significantly in patients with GC. PGD2 suppressed viability, invasion, and stemness and increased the apoptosis of GCSCs. Downregulating L-PTGDS and PTGDR2 promoted viability, invasion, and stemness and reduced the apoptosis of GCSCs. Moreover, the inhibition of GCSCs induced by PGD2 was eliminated by downregulating the expression of PTGDR2. The results of in vivo experiments were consistent with those of in vitro experiments. Our data suggest that PGD2 may be an important marker and potential therapeutic target in the clinical management of GC. L-PTGDS/PTGDR2 may be one of the critical targets for GC therapy. The PGD2/PTGDR2 signal affects the viability, invasion, apoptosis, and stemness of GCSCs and prevents the progression of GC.

GALNT2 targeted by miR-139-5p promotes proliferation of clear cell renal cell carcinoma via inhibition of LATS2 activation

Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3ʹ UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.

RPN1 promotes the proliferation and invasion of breast cancer cells by activating the PI3K/AKT/mTOR signaling pathway

Ribophorin I (RPN1), a part of an N-oligosaccharyl-transferase complex, plays a vital role in the development of multiple cancers. However, its biological role in breast cancer has not been completely clarified. The RPN1 expression level was measured in breast cancer tissues and breast cancer cell lines (MCF7) using RT-qPCR. After down-regulating RPN1 expression by shRNA, the effects of RPN1 on the proliferation, migration and invasion of MCF7 cells were examined. Mechanistically, we assessed the effect of RPN1 on the PI3K/ AKT/mTOR signaling pathway. We found that RPN1 level was up-regulated in breast cancer tissues and cells compared with adjacent non-tumor tissues or MCF10A cells. RPN1 knockdown induced apoptosis and attenuated the proliferation, migration, and invasion of MCF7 cells. Moreover, RPN1 knockdown lowered the levels of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR, which were rescued by 740Y-P, a PI3K activator. 740Y-P also reversed the effects of RPN1 knockdown on apoptosis, proliferation, migration, and invasion in MCF7 cells. Taken together, RPN1 promotes the proliferation, migration, and invasion of breast cancer cells via the PI3K/AKT/mTOR signaling pathway.

Squalene monooxygenase facilitates bladder cancer development in part by regulating PCNA

Bladder cancer (BC) is one of the most common cancers worldwide. Although the treatment and survival rate of BC are being improved, the risk factors and the underlying mechanisms causing BC are incompletely understood. Squalene monooxygenase (SQLE) has been associated with the occurrence and development of multiple cancers but whether it contributes to BC development is unclear. In this study, we performed bioinformatics analysis on paired BC and adjacent non-cancerous tissues and found that SQLE expression is significantly upregulated in BC samples. Knockdown of SQLE impairs viability, induces apoptosis, and inhibits the migration and invasion of BC cells. RNA-seq data reveals that SQLE deficiency leads to dysregulated expression of genes regulating proliferation, migration, and apoptosis. Mass spectrometry-directed interactome screening identifies proliferating cell nuclear antigen (PCNA) as an SQLE-interacting protein and overexpression of PCNA partially rescues the impaired viability, migration, and invasion of BC cells caused by SQLE knockdown. In addition, we performed xenograft assays and confirmed that SQLE deficiency inhibits BC growth in vivo. In conclusion, these data suggest that SQLE promotes BC development and SQLE inhibition may be therapeutically useful in BC treatment.

Molecular basis and current insights of atypical Rho small GTPase in cancer.

Atypical Rho GTPases are a subtype of the Rho GTPase family that are involved in diverse cellular processes. The typical Rho GTPases, led by RhoA, Rac1 and Cdc42, have been well studied, while relative studies on atypical Rho GTPases are relatively still limited and have great exploration potential. With the increase in studies, current evidence suggests that atypical Rho GTPases regulate multiple biological processes and play important roles in the occurrence and development of human cancers. Therefore, this review mainly discusses the molecular basis of atypical Rho GTPases and their roles in cancer. We summarize the sequence characteristics, subcellular localization and biological functions of each atypical Rho GTPase. Moreover, we review the recent advances and potential mechanisms of atypical Rho GTPases in the development of multiple cancers. A comprehensive understanding and extensive exploration of the biological functions of atypical Rho GTPases and their molecular mechanisms in tumors will provide important insights into the pathophysiology of tumors and the development of cancer therapeutic strategies.

Identification and Validation of a Cancer-Testis Antigen-Related Signature to Predict the Prognosis in Stomach Adenocarcinoma.

Background: Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate in the pathogenesis and development of multiple cancers and are aberrantly overexpressed in various types of cancer. This study aimed to develop a CTA-related gene signature (CTARSig) to predict prognosis in STAD patients and explore its underlying mechanisms. Methods: We performed differential and prognostic analyses of CTA-related genes and constructed a CTA-related signature (CTARSig) along with a novel nomogram to predict the prognosis of patients with STAD based on the Cox and The Least Absolute Shrinkage and Selection Operator. CTARSig was further validated in an external cohort (GSE84437). Additionally, univariate and multivariate Cox regression, as well as receiver operating characteristic (ROC) analyses, were performed to assess the CTARSig systematically. Single-sample gene set enrichment analysis and ESTIMATE were used to characterise the Tumor Immune Microenvironment (TIME) in patients with STAD. Furthermore, Gene Set Variation Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology analyses revealed the biological functions and signalling pathways associated with CTARSig. Finally, the human gastric cancer cell lines, HCG-27 and AGS, were used for in vitro and in vivo experiments, respectively, to further validate the role of ELOVL4. Results: Eleven CTA-related genes were identified to construct the CTARSig. Kaplan-Meier curves, independent prognostic analysis, and ROC curves revealed that CTARSig could better predict survival in patients with STAD. Moreover, in our study, we demonstrated that ELOVL4 is upregulated in gastric cancer tissues and that its high expression is associated with poor survival. Additionally, in vitro and in vivo experiments demonstrated that ELOVL4 promotes the metastatic and invasive potential of STAD cells, suggesting it may be a potential therapeutic target for STAD. Conclusion: In this study, a novel signature associated with CTAs was constructed for STAD, which may be a good predictor of patient prognosis. Thus, ELOVL4 may be a potential therapeutic target for gastric cancer. This study provides new insights into the potential roles of CTAs in gastric cancer.

Mass Spectrometry-Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine.

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.

Exploring the diagnostic value, prognostic value, and biological functions of NPC gene family members in hepatocellular carcinoma based on a multi-omics analysis.

Liver cancer is a cunning malignancy with a high incidence and mortality rate among cancers worldwide. The NPC gene family members (NPCs: NPC1, NPC2, and NPC1L1) are closely linked to the development of multiple cancers, but their role in liver cancer remains unclear. As a result, we must investigate their functions in liver hepatocellular carcinoma (LIHC). NPCs were significantly differentially expressed between normal and LIHC tissues, with a high mutation frequency in LIHC. The ROC curve analysis revealed that NPC1/NPC2 had high diagnostic and prognostic values in LIHC. NPC1 expression was also found to be negatively correlated with its methylation level. The differentially expressed genes between high and low NPC1 expression groups in LIHC were mainly related to channel activity, transporter complexes, and plasma membrane adhesion molecules. Additionally, NPC1 expression was significantly associated with multiple immune cells and immunization checkpoints. It was hypothesized that a TUG1/SNHG4-miR-148a-3p-NPC1 regulatory axis is associated with hepatocarcinogenesis. Finally, the protein expression of NPC1 in LIHC tissues and paraneoplastic tissues was detected, and NPC1-knockdown HepG2 cells (NPC1KO) inhibited the proliferation, migration, and invasion. This study helped to identify new prognostic markers and potential immunotherapeutic targets for LIHC and revealed the molecular mechanisms underlying NPC1 regulation in LIHC. The NPCs play a key role in the prognosis and diagnosis of LIHC and may be an important indicator for LIHC prognosis and diagnosis; NPC1 might be a potential therapeutic target in LIHC.

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

BackgroundCancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung.MethodsExome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case–control association analyses were performed.ResultsAltogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations.ConclusionsWe have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma.

Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.

Incident Diabetes By Obesity-Related Cancer Status and Cancer Treatment Type: A Prospective Study Using Electronic Medical Records Data

Background: Diabetes has been associated with an increased risk of the development of multiple cancers, however evidence for development of diabetes after cancer diagnosis is limited. Methods: Using data on 7,702 cancer patients treated at the Huntsman Cancer Institute, a comprehensive cancer center in Utah, we examined the association of systemic cancer treatments (chemotherapy, immunotherapy, hormone therapy, and corticosteroids) and obesity-related cancer (ORC) status with the development of diabetes after cancer diagnosis. Cox proportional-hazards models adjusting for relevant covariates [age, sex, race, body mass index at cancer diagnosis, and ORC status (in treatment–related models only)] were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Diabetes, cancer treatments, and cancer sites were identified using ICD codes and tumor histology. Results: 975(12.7%) cancer patients had incident diabetes (723 type-2 diabetes), and the mean time to diabetes diagnosis was 4.4 years after cancer diagnosis. 35.1% cancer patients received chemotherapy, 11.8% received immunotherapy, 19.5% received hormone therapy, 38.8% received corticosteroids, and 40.8% were diagnosed with an ORC. ORC patients and corticosteroid users had a statistically significant elevated risk of new-onset diabetes [HR (95% CI) = 1.43 (1.24–1.65) and 1.29 (1.13–1.47), respectively] compared to patients with a non-ORC and non-users of corticosteroids. Interestingly, patients who received chemotherapy or hormone therapy had a statistically significant lower risk of new-onset diabetes [HR(95% CI) = 0.69 (0.60–0.79) and 0.68 (0.58–0.81), respectively] compared to patients who did not receive these treatments. Stratified analyses evaluating death as a competing risk factor are ongoing. Conclusion: We observed statistically significant 1.43-times and 1.29-times increased risk of incident diabetes after cancer diagnosis in ORC patients and corticosteroid users. These results suggest that certain cancer treatments may increase diabetes risk. As monitoring cancer patients for new onset diabetes is currently not a clinical standard, understanding diabetes risk in cancer patients can inform strategies for monitoring cancer patients to prevent diabetes development.

ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models.

E3 ubiquitin ligase Zinc and Ring Finger 2 (ZNRF2) has been demonstrated to be engaged in the development of multiple cancers. Nevertheless, the function of ZNRF2 in breast cancer (BC) still unclear. In this work, we firstly analyzed the differentially expressed genes in BC by bioinformatics and found that ZNRF2 was highly expressed in BC. Consistently, we further confirmed that ZNRF2 was upregulated in BC tissues compared with adjacent normal tissues, and this was positively correlated with the poor prognosis and the higher pathological grades of patients with BC. Functional assays performed on HCC1937 and MCF-7 cells indicated that silencing of ZNRF2 suppressed cell proliferation, as evidenced by the decrease in the expression of cyclin A, PCNA and cyclin D1. Flow cytometry and Hoechst staining showed that knockdown of ZNRF2 induced cell apoptosis, which was verified by the upregulation of apoptosis genes such as Bax, cleaved PARP and Bim. ZNRF2 knockdown also inhibited in vivo tumor growth. But, instead, ZNRF2-overexpressed BC cells exhibited obvious malignant phenotypes. Additionally, we observed that cAMP response element binding protein 1 (CREB1) directly bound to the promoter sequence of ZNRF2 and thus activating its transcription, suggesting that ZNRF2 is transcriptionally regulated by CREB1. Additionally, ZNRF2 knockdown could reverse the proliferation-promoting action of CREB1 on BC cells, Hence, this study demonstrated that ZNRF2 might serve as a prospective therapeutic target for BC.

Nanobody Loop Mimetics Enhance Son of Sevenless 1-Catalyzed Nucleotide Exchange on RAS.

RAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active guanosine triphosphate (GTP)-bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14 (Nb14), which potently enhances SOS1-catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity-determining region 3 (CDR3). Guided by a biochemical GEF assay and X-ray co-crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of Nb14 with an EC50 value of 29 μM. Altogether, this study demonstrated that peptides able to modulate a protein-protein interaction can be obtained by structural mimicry of a Nb paratope.

Nanobody Loop Mimetics Enhance Son of Sevenless 1‐Catalyzed Nucleotide Exchange on RAS**

AbstractRAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active guanosine triphosphate (GTP)‐bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14 (Nb14), which potently enhances SOS1‐catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity‐determining region 3 (CDR3). Guided by a biochemical GEF assay and X‐ray co‐crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of Nb14 with an EC50 value of 29 μM. Altogether, this study demonstrated that peptides able to modulate a protein‐protein interaction can be obtained by structural mimicry of a Nb paratope.

A hidden translatome in tumors-the coding lncRNAs.

Long noncoding RNAs (lncRNAs) have been extensively identified in eukaryotic genomes and have been shown to play critical roles in the development of multiple cancers. Through the application and development of ribosome analysis and sequencing technologies, advanced studies have discovered the translation of lncRNAs. Although lncRNAs were originally defined as noncoding RNAs, many lncRNAs actually contain small open reading frames that are translated into peptides. This opens a broad area for the functional investigation of lncRNAs. Here, we introduce prospective methods and databases for screening lncRNAs with functional polypeptides. We also summarize the specific lncRNA-encoded proteins and their molecular mechanisms that promote or inhibit cancerous. Importantly, the role of lncRNA-encoded peptides/proteins holds promise in cancer research, but some potential challenges remain unresolved. This review includes reports on lncRNA-encoded peptides or proteins in cancer, aiming to provide theoretical basis and related references to facilitate the discovery of more functional peptides encoded by lncRNA, and to further develop new anti-cancer therapeutic targets as well as clinical biomarkers of diagnosis and prognosis.

Abstract 741: Incident diabetes by obesity-related cancer status and cancer treatment type

Abstract Background: Diabetes has been associated with an increased risk of the development of multiple cancers, however, evidence for development of diabetes after cancer diagnosis is limited. Methods: Using data on 7,702 cancer patients treated at the Huntsman Cancer Institute, a comprehensive cancer center in Utah, we examined the association of systemic cancer treatments (chemotherapy, immunotherapy, hormone therapy, and corticosteroids) and obesity-related cancer (ORC) status (presence of breast, colorectal, ovarian, endometrial, kidney, thyroid, meningioma, multiple myeloma, gallbladder, gastric cardia, esophageal adenocarcinoma, liver, or pancreatic cancer), with the development of diabetes after cancer diagnosis. Cox proportional-hazards regression models adjusting for relevant covariates [age, sex, race, body mass index at cancer diagnosis, and ORC status (in treatment-related models only)] were used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Diabetes, cancer treatment type, and cancer sites were identified using ICD codes and tumor histology. Results: 975(12.7%) cancer patients had incident diabetes (723 of which were type-2 diabetes), and the average time to diabetes diagnosis after cancer diagnosis was 4.4 years. 35.1% used chemotherapy, 11.8% used immunotherapy, 19.5% used hormone therapy, 38.8% used corticosteroids, and 40.8% had an ORC. ORC patients and patients who used corticosteroids had a statistically significant higher hazard of new-onset diabetes [HR(95% CI) 1.43(1.24-1.65), 1.29(1.13-1.47), respectively] compared to patients with a non-ORC and patients who did not use corticosteroids, respectively. Interestingly, patients who received chemotherapy or hormone therapy had a statistically significant lower hazard of new-onset diabetes [HR(95% CI) 0.69(0.60-0.79), 0.68(0.58-0.81), respectively] compared to patients who did not receive chemotherapy or hormone therapy, respectively. Analyses by cancer site and diabetes type and evaluating death as a competing risk factor are ongoing. Conclusions: We observed statistically significant 1.43-times and 1.29-times higher hazards of incident diabetes after cancer diagnosis in ORC patients and corticosteroid users. These results suggest that certain cancers and cancer treatments may increase diabetes risk. As monitoring cancer patients for persistent hyperglycemia and diabetes is currently not a clinical standard, understanding the risk of chronic diseases, including diabetes, can inform strategies to monitor patients and decrease disease burden in this vulnerable population. Citation Format: Maci Winn, Svenja Pauleck, Richard Viskochil, Stephanie Richardson, Michelle Litchman, Howard Colman, Neli Ulrich, Siwen Hu-Lieskovan, Mary Playdon, Sheetal Hardikar. Incident diabetes by obesity-related cancer status and cancer treatment type [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 741.

LncRNA-MIAT activates hepatic stellate cells via regulating Hippo pathway and epithelial-to-mesenchymal transition

Long non-coding RNA-myocardial infarction-associated transcript (lncRNA-MIAT) has been reported to play an important role in the development of multiple cancers. However, the biological roles of MIAT in liver fibrosis are still unknown. In this study, the expression of MIAT is up-regulated during liver fibrosis. Silencing MIAT leads to the suppression of hepatic stellate cell (HSC) proliferation and collagen expression. Double immunofluorescence analysis additionally demonstrates that MIAT inhibition leads to the suppression of type I collagen and α-SMA in vitro. In vivo, MIAT knockdown contributes to the inhibition of fibrosis progression and collagen accumulation. MIAT is confirmed as a target of miR-3085-5p, and the co-location of MIAT and miR-3085-5p is found in HSC cytoplasm. Interestingly, there is a negative correlation between MIAT expression and miR-3085-5p level in cirrhotic patients as well as activated HSCs. In addition, the effects of MIAT inhibition on HSC inactivation are blocked down by miR-3085-5p inhibitor. YAP is a target of miR-3085-5p. Reduced YAP caused by loss of MIAT is reversed by miR-3085-5p inhibitor. Notably, YAP knockdown results in the suppression of MIAT-mediated epithelial-to-mesenchymal transition (EMT) process. In conclusion, we demonstrate that MIAT enhances the activation of HSCs, at least in part, via miR-3085-5p/YAP/EMT signaling pathway.

MORC4 plays a tumor-promoting role in colorectal cancer via regulating PCGF1/CDKN1A axis in vitro and in vivo.

MORC family CW-type zinc finger 4 (MORC4) possessing nuclear matrix binding domains has been observed to be involved in multiple cancer development. By digging three gene expression omnibus (GEO) gene microarrays (GSE110223, GSE110224 and GSE24514), we found that MORC4 was overexpressed in colorectal cancer (CRC) samples (log2 Fold change >1, p < 0.05). We aimed to investigate the role of MORC4 in CRC malignant behaviors, with an emphasis on polycomb group ring finger 1 (PCGF1)/cyclin-dependent kinase inhibitor 1A (CDKN1A) axis. Firstly, we confirmed MORC4 as an upregulated gene in 60 pairs of frozen CRC and adjacent normal samples. MORC4 overexpression increased proliferation and metastasis, and decreased apoptosis in SW480 and HT29 cells, which was diminished by the knockdown of PCGF1, a transcriptional repressor of CDKN1A (a potent cyclin-dependent kinase inhibitor). MORC4 was further identified as a novel molecule that interacted with PCGF1 via coimmunoprecipitation. MORC4 itself did not substantially suppress CDKN1A transcriptional activity, but it augmented PCGF1's effect on CDKN1A. Additionally, MORC4 acted as the substrate of HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) and was degraded through ubiquitin-proteasome system. Collectively, our work suggested that MORC4 accelerated CRC progression via governing PCGF1/CDKN1A signaling.