Multiple myeloma (MM) is a hematological malignancy worldwide in urgent need for novel therapeutic strategies. Since Velcade (bortezomib) was approved for the treatment of relapsed/refractory MM in 2003, we have seen considerable improvement in extending MM patient survival. However, most patients are fraught with high recurrence rate and incurability. Acupuncture is known for alleviating patient symptoms and improving the quality of life, but it is not well investigated in MM, especially in combination with bortezomib. In this study, we employed LC-MS and UHPLC-MS together with bioinformatics methods to test serum samples from 5TMM3VT MM murine model mice with four different treatments [control (C) group, bortezomib (V) treatment group, acupuncture (A) group, and combined (VA) group]. MM mice in group VA had longer survival time than mice in group A or group V. Joint pathway analysis indicated the underlying arginine and proline metabolism pathway among the 32 significantly decreased metabolites in group VA. CCK-8 assay and in vivo experiments validated that ornithine, the metabolite of arginine, promoted MM cell proliferation. In addition, gene expression omnibus (GEO) database analysis suggested that MM patients with higher ornithine decarboxylase 1 (ODC1) expression were evidently associated with poor overall survival. In summary, this study demonstrates the synergistic effects of acupuncture and bortezomib on extending the survival of MM model mice and provides potential therapeutic targets in the treatment of MM.

Ebola virus, a member of the Filoviridae family, utilizes the attachment factors on host cells to support its entry and cause severe tissue damage. TIM-1 has been identified as a predominant attachment factor via interaction with phosphatidylserine (PS) localized on the viral envelope and glycoprotein (GP). In this study, we give the first demonstration that TIM-1 enhances the cellular entry of three species of Ebola virus, as well as those harboring GP mutations (A82V, T544I, and A82V T544I). Furthermore, two TIM-1 variants (i.e., TIM-1-359aa and TIM-1-364aa) had comparable effects on promoting Zaire Ebola virus (EBOV) attachment, internalization, and infection. Importantly, recombinant TIM-1 ectodomain (ECD) protein could decrease the infectivity of Ebola virus and display synergistic inhibitory effects with ADI-15946, a monoclonal antibody with broad neutralizing activity to Ebola virus. Of note, EBOV strains harboring GP mutations (K510E and D552N), which were refractory to antibody treatment, were still sensitive to TIM-1 protein-mediated impairment of infectivity, indicating that TIM-1 protein may represent an alternative therapeutic regimen when antibody evasion occurs. IMPORTANCE The viral genome has acquired numerous mutations with the potential to increase transmission during the 2013-to-2016 outbreak of Ebola virus. EBOV strains harboring GP mutations (A82V, T544I, and A82V T544I), which have been identified to increase viral infectivity in humans, have attracted our attention. Herein, we give the first report that polymorphic TIM-1 enhances the infectivity of three species of Ebola virus, as well as those harboring GP mutations (A82V, T544I, and A82V T544I). We show that recombinant TIM-1 ECD protein could decrease the infectivity of Ebola virus with or without a point mutation and displays synergistic inhibitory effects with ADI-15946. Furthermore, TIM-1 protein potently blocked cell entry of antibody-evading Ebola virus species. These findings highlight the role of TIM-1 in Ebola virus infection and indicate that TIM-1 protein represents a potential therapeutic avenue for Ebola virus and its mutated species.

Introduction: Thyroid cancer is the most common endocrine malignancy with Papillary Thyroid Carcinoma (PTC) as the most common pathological type. Due to low mortality but a high incidence, PTC still causes a relatively heavy burden on financial costs, human health, and quality of life. Emerging researches have indicated that circular RNAs (circRNAs) play a significant regulatory role in various cancers, including PTC. However, the functions and mechanisms of circRNAs derived from SSU72 remain unknown. Method: The expression level of circRNAs derived from the exons of SSU72, miR-361-3p, miR-451a, and S1PR2 was evaluated by qRT-PCR assay or western blot assay. The interactions between circSSU72 (hsa_circ_0009294), miR-451a, and S1PR2 were verified by dual-luciferase reporter assay. Effects of circSSU72, miR-451a, and S1PR2 on cell proliferation, migration, and invasion were confirmed by colony formation assay, cell counting kit-8 (CCK-8), wound healing assay, and Transwell assays in vitro. Results: circSSU72 was upregulated in PTC; circSSU72 knockdown inhibited PTC cell proliferation, migration, and invasion. In addition, circSSU72 could negatively regulate miR-451a by functioning as a sponge. circSSU72 promoted PTC cell proliferation, migration, and invasion by targeting miR-451a in vitro. We further found that miR-451a inhibited PTC cell proliferation, migration, and invasion by regulating S1PR2. Overall, the circSSU72/miR-451a/S1PR2 axis might influence PTC cell proliferation, migration, and invasion. Conclusions: Overall, circSSU72 (hsa_circ_0009294)/miR-451a/S1PR2 axis may promote cell proliferation, migration, and invasion in PTC. Thus, circSSU72 may serve as a potential biomarker and therapeutic target for PTC.

1,4-Dioxane (dioxane), an industrial solvent widely detected in environmental and biological matrices, has potential nephrotoxicity. However, the underlying mechanism by which dioxane induces kidney damage remains unclear. In this study, we used an integrated approach, combining kidney transcriptomics and urine metabolomics, to explore the mechanism for the toxic effects of dioxane on the mouse kidney. Transcriptomics profiling showed that exposure to 0.5 mg/L dioxane induced perturbations of multiple signaling pathways in kidneys, such as MAPK and Wnt, although no changes in oxidative stress indicators or anatomical pathology were observed. Exposure to 500 mg/L dioxane significantly disrupted various metabolic pathways, concomitantly with observed renal tissue damage and stimulated oxidant defense system. Urine metabolomic analysis using NMR indicated that exposure to dioxane gradually altered the metabolic profile of urine. Within the full range of altered metabolites, the metabolic pathway containing glycine, serine and threonine was the most significantly altered pathway at the early stage of exposure (3 weeks) in both 0.5 and 500 mg/L dioxane-treated groups. However, with prolonged exposure (9 and 12 weeks), the level of taurine significantly decreased after treatment of 0.5 mg/L dioxane, while exposure to 500 mg/L dioxane significantly increased glutathione levels in urine and decreased arginine metabolism. Furthermore, integrated omics analysis showed that 500 mg/L dioxane exposure induced arginine deficiency by perturbing several genes involved in renal arginine metabolism. Shortage of arginine coupled with increased oxidative stress could lead to renal dysfunction. These findings offer novel insights into the toxicity of dioxane.

Adolescence is a critical period for the vulnerability of anxiety. Imaging studies focusing on adolescents' susceptibility to anxiety suggest that the different development trajectories between the limbic system and the executive control system may play important roles in this phenomenon. However, few studies have explored the brain basis of this susceptibility from the perspective of functional networks. The salience network (SN) consists of a series of key limbic and prefrontal regions that are engaged in the development of anxiety, such as the amygdala, anterior insula (AI), and dorsal anterior cingulate cortex (dACC). Intra- and inter-network connections in this system play essential roles in bottom-up attention and top-down regulation of anxiety, nevertheless, little is known about whether the SN-centered connections are associated with trait anxiety (i.e., susceptibility to anxiety) in adolescents.

Papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a newly identified non-coding RNA, which is highly thyroid-specific. Dramatic downregulation in thyroid cancers suggests its potential roles in the occurrence and development of thyroid tumors. The present study aimed to investigate the effects of PTCSC3 on the biological features of thyroid cancer cells and to explore its possible function as a competing endogenous RNA to bind with miRNAs. Constructs containing the long non-coding RNA, PTCSC3, were transfected into various thyroid cancer cell lines (BCPAP, FTC133 and 8505C). Cell growth, cell cycle transition and apoptosis were measured by MTT assay and flow cytometry. In silico analysis was performed to identify the binding site of PTCSC3 for target miRNAs. Additionally, detection of putative miRNA by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in thyroid cancer cells transfected with PTCSC3 was determined to confirm the interaction. Following transfection with PTCSC3, all three thyroid cancer cells originating from various pathological types of thyroid cancers demonstrated significant growth inhibition, cell cycle arrest and increased apoptosis. The top 20 miRNAs to have a potential interaction with PTCSC3 were identified, out of which miR-574-5p was selected to further confirm the inverse correlation with PTCSC3 in thyroid cancer cells in vitro. In the present study, PTCSC3 as a tumor suppressor was investigated as a competing endogenous RNA for miR-574-5p.

Herein, we present a new bacterial strain isolated from infected blood of a patient with diabetic nephropathy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry failed to identify the strain. 16S rRNA gene sequencing showed the highest similarity (>99.5%) with genus Dysgonomonas, but the strain could not be distinguished from Dysgonomonas oryzarvi and Dysgonomonas mossii. Whole genome sequencing, followed by phylogenetic analysis and average nucleotide identity (>95%) analysis, confirmed that the new strain represented Dysgonomonas mossii, leading it to be named Dysgonomonas mossii strain Shenzhen WH 0221. Shenzhen WH 0221 was 3.60 Mb with 37.4% GC content. It was Gram-stain negative, facultatively anaerobic, and grown on Columbia agar supplemented with 5% of sheep blood, exhibiting a smooth surface and pinpoint morphology. The morphological characteristics of this strain include a short rod shape without flagella and a size of 0.45-0.55 × 0.95-1.52 μm observed under transmission electron microscopy. The physiological and biochemical features and major cellular fatty acids (characterized by C14:0 3-OH, C14:0 9-CH3, and C16:0) differed from D. mossii CCUG 43457T and other members of the genus Dysgonomonas. The isolate was found resistant to most cephalosporins, penicillin, norfloxacin, vancomycin, and chloramphenicol, but was susceptible to meropenem, imipenem, tetracycline, clindamycin, and amoxicillin-clavulanic acid. Genes kdpE, ykkD, cmeB, TLA-3, and vanRM found in its genome are probably associated with multiple antibiotic resistance. Lipopolysaccharides, capsules, and cytolysin may also help to illuminate its potential pathogenicity. This is the first report of a case of sepsis caused by Dysgonomonas mossii, and its pathogenic system was analyzed by whole genome sequencing. IMPORTANCE This study identified a new strain, Dysgonomonas mossii strain Shenzhen WH 0221, which has been first reported to cause sepsis isolated from infected blood of a patient with diabetic nephropathy. Physiological and biochemical characterizations, as well as overall fatty acid profile, distinguish Shenzhen WH 0221 from other species of the same genus. However, limited antibiotics were researched for Dysgonomonas mossii. Seventeen antibiotics spanning at least 6 classes were studied, providing a valuable guide to the clinical usage of drugs to treat Dysgonomonas mossii infection. For the first time, we report genome-based functional predictions for Dysgonomonas mossii. Five antibiotic resistance ontologies and more than 200 virulence factors likely underlie the multidrug resistance of Shenzhen WH 0221 and its potential pathogenicity.

Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival.

Hepatocellular carcinoma (HCC) is a common malignancy in the world, with high mortality and poor prognosis. Hepatitis B virus (HBV) is one of the key factors implicated in the occurrence of HCC. Increasing evidence suggests that miRNAs play important roles in the development and metastasis of HBV-associated HCC (HBV-HCC). Here, we performed CCK8 (Cell count kit-8), EdU (5-ethynyl-2'-deoxyuridine) incorporation assay, wound-healing assay, transwell assay to study the changes in the cellular phenotype. Luciferase reporter assay, RNA pull-down experiment, RT-qPCR and western blotting were employed to study molecular mechanism. In addition, we also constructed a mouse HCC xenograft model to verify the functional role of HMMR-AS1/miR-627-3p/HMGA2 signal axis in vivo. Our study demonstrated that HMMR-AS1 was highly expressed in HCC tissues and cell lines, suggesting its implication in the progression of HCC. In addition, in vitro experiments showed that high HMMR-AS1 expression facilitated the migration, invasion, and proliferation of HCC cells. We further revealed that HMMR-AS1 promoted the malignant phenotype of HCC cells by regulating miR-627-3p/HMGA2 axis. Together, our data suggest that HMMR-AS1 regulates HBV-HCC progression via miR-627-3p/HMGA2 axis.

Thyroid cancer is an endocrine malignancy that is growing in incidence worldwide. Despite progress in diagnostics and treatment of thyroid cancer, prognosis remains poor. Emerging research has shown that circular RNAs (circRNAs) have crucial regulatory roles in cancers. However, the possible functions and mechanisms of hsa_circ_0011385 remain undetermined.

Distant metastasis (DM) is not common in differentiated thyroid cancer (DTC). However, it is associated with a significantly poor prognosis. Early detection of high-risk DTC patients is difficult, and the molecular mechanism is still unclear. Therefore, the present study aims to establish a novel predictive model based on clinicopathological parameters and DM-related gene signatures to provide guidelines for clinicians in decision making.

Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression.

The Warburg effect (aerobic glycolysis), a hallmark of cancer, serves as a promising target for diagnosis and therapy. Growing evidence indicates that long non-coding RNAs (lncRNAs) play an important role in aerobic glycolysis of various tumours. However, the correlation between lncRNAs and glycolysis in thyroid cancer cells is still poorly understood. In this study, we showed that lncRNA papillary thyroid cancer susceptibility candidate 3 (PTCSC3) was significantly downregulated in papillary thyroid carcinoma (PTC). Overexpression of PTCSC3 significantly inhibited the aerobic glycolysis and tumour growth of PTC cells. Consistently, PTCSC3 overexpression suppressed tumour progress in vivo. Mechanistically, PTCSC3 inhibits aerobic glycolysis and proliferation of PTC by directly interacting with PGK1, a key enzyme in glycolytic pathway. As a result, PTCSC3 performs its role in PTC development via PGK1 and may be a potential therapeutic target for PTC treatment.

Propofol, an intravenous anesthetic agent, exerts an anti-tumor peculiarity in multifarious tumors. Circular RNA hsa_circ_0000735 (circ_0000735) is involved in non-small cell lung cancer (NSCLC) progression. The purpose of this study is to investigate whether propofol can curb NSCLC progression via regulating circ_0000735 expression. Cell viability, proliferation, apoptosis, and invasion were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine, flow cytometry, and transwell assays. Evaluation of protein levels was performed using western blotting or immunohistochemistry. Detection of circ_0000735 in tissue samples and cells was carried out using a real-time quantitative polymerase chain reaction. The molecular mechanisms associated with circ_0000735 were predicted by bioinformatics analysis and verified by dual-luciferase reporter assays. The relationship between propofol and circ_0000735 in vivo was verified by xenograft models. The results showed that circ_0000735 was overexpressed in NSCLC samples and cells. Propofol treatment overtly decreased circ_0000735 expression in NSCLC cells and repressed NSCLC cell viability, proliferation, invasion, and facilitated NSCLC cell apoptosis, but these effects mediated by propofol were counteracted by circ_0000735 overexpression. Circ_0000735 functioned as a miR-153-3p sponge and regulated integrin-β1 (ITGB1) expression via adsorbing miR-153-3p. ITGB1 overexpression reversed circ_0000735 silencing-mediated effects on NSCLC cell viability, proliferation, invasion, and apoptosis. In conclusion, propofol restrained NSCLC growth by downregulating circ_0000735, which functioned as a miR-153-3p sponge and regulated ITGB1 expression via adsorbing miR-153-3p. This study provides evidence to support that propofol curbs NSCLC progression by regulating circRNA expression.

Translation dysregulation plays a crucial role in tumourigenesis and cancer progression. Oncogenic translation relies on the stability and availability of tRNAs for protein synthesis, making them potential targets for cancer therapy.

Extrathyroidal extension (ETE) affects papillary thyroid cancer (PTC) prognosis. The objective of this study was to identify biomarkers for ETE and explore the mechanisms controlling its development in PTC. We performed a comprehensive bioinformatics analysis using several datasets. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) on 58 paired PTC samples from The Cancer Genome Atlas (TCGA) were used to detect ETE-related mRNA and long noncoding (lnc) RNA modules and construct an lncRNA/mRNA network. An independent TCGA dataset containing 438 samples was utilized to validate and characterize the WGCNA results. Functional annotation was used to identify the biological functions and related pathways of ETE modules. Two independent RNA sequencing datasets were combined to crossvalidate relationships between lncRNAs and mRNAs by Pearson correlation analysis. Transcription factors (TFs) for affected genes were predicted using the binding motif data from Ensembl Biomart to construct a TF/lncRNA/mRNA network. Other two independent datasets were used to crossvalidate TF-mRNA associations. Finally, receiver operating characteristic, survival analyses, and Cox proportional hazard regression model were performed to explore the significance of hub genes in ETE diagnosis and PTC prognosis. Three mRNA modules and two lncRNA modules were significantly associated with ETE. Enrichment analysis showed extracellular matrix changes was closely related to the development of ETE. A TF/lncRNA/mRNA regulatory network was constructed containing 33 validated hub genes, 64 lncRNAs, and 64 TFs, all differentially expressed between ETE and non-ETE samples. Unc-5 family C-terminal like [area under the curve (AUC): 0.711], sushi repeat containing protein X-linked 2 (AUC: 0.706), lysyl oxidase (AUC: 0.704), collagen type I alpha 1 chain (AUC: 0.704), and collagen type X alpha 1 chain (AUC: 0.704) were the most highly significant hub genes for ETE diagnosis. The Cox proportional hazard regression model constructed with hub genes showed significant survival differences between low- and high-risk groups (p = 0.00025) and performed good prediction for PTC prognosis(AUC = 0.794; C-index = 0.895). The identification of 33 biomarkers and TF/lncRNA/mRNA regulatory network would provide new insights into the molecular mechanisms of ETE besides the prognosis model may have important clinical implications in the improvement of PTC risk stratification, therapeutic decision-making, and prognosis prediction.

Background: CDK12 is a potential therapeutic target in papillary thyroid cancer that regulates the c-myc/β-catenin pathway. Objective: We aimed to explore the specific mechanism of CDK12 in papillary thyroid cancer and provide a new target of cancer therapy. Methods: RT-qPCR was used to determine the CDK12 mRNA expression level. An IHC assay was performed to detect the tissue expression of CDK12. Then, we downregulated CDK12 expression in the thyroid cancer cell lines TPC-1-shCDK12 and KAT-5-shCDK12. CCK8 assays, colony formation assays, and animal xenograft models were used to evaluate the effect of CDK12 on tumorigenesis. Transwell assays and in vivo metastasis models were used to observe whether CDK12 can promote cancer metastasis. Western blotting further confirmed the mechanism of CDK12 in papillary thyroid cancer through the c-myc/β-catenin pathway. Results: Upregulated CDK12 expression in papillary thyroid cancer promoted papillary thyroid cancer carcinogenesis in vivo, and in vitro CDK12 strengthened papillary thyroid cancer (PTC) cell migration and tumor metastasis. CDK12 promoted tumor progression by regulating c-myc/β-catenin pathway activation. Conclusions: CDK12 affects the c-myc/β-catenin pathway to stimulate papillary thyroid cancer proliferation and metastasis. Inhibiting CDK12 might be a new method in papillary thyroid cancer therapy.

The tumor stroma plays an important role in tumor progression and chemotherapeutic resistance; however, its role in colon cancer (CC) survival prognosis remains to be investigated. Here, we identified tumor stroma biomarkers and evaluated their role in CC prognosis stratification. Four independent datasets containing a total of 1,313 patients were included in this study and were divided into training and testing sets. Stromal scores calculated using the estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) algorithm were used to assess the tumor stroma level. Kaplan-Meier curves and the log-rank test were used to identify relationships between stromal score and prognosis. Tumor stroma biomarkers were identified by cross-validation of multiple datasets and bioinformatics methods. Cox proportional hazards regression models were constructed using four prognosis factors (age, tumor stage, the ESTIMATE stromal score, and the biomarker stromal score) in different combinations for prognosis prediction and compared. Patients with high stromal scores had a lower overall survival rate (p = 0.00016), higher risk of recurrence (p < 0.0001), and higher probability of chemotherapeutic resistance (p < 0.0001) than those with low scores. We identified 16 tumor stroma biomarkers and generated a new prognosis indicator termed the biomarker stromal score (ranging from 0 to 16) based on their expression levels. Its addition to an age/tumor stage-based model significantly improved prognosis prediction accuracy. In conclusion, the tumor stromal score is significantly negatively associated with CC survival prognosis, and the new tumor stroma indicator can improve CC prognosis stratification.

The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl-ECD), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl-ECD. Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.

Multiple myeloma (MM) is an incurable plasma cell malignancy, while CAR-T therapy offers a new direction for the treatment of MM. Recently, signaling lymphocytic activation molecule family 3 (CD229), a cell surface immune receptor belonging to the signaling lymphocyte activating molecule family (SLAMF), is emerging as a CAR-T therapeutic target in MM. However, a clear role of CD229 in MM remains elusive. In this study, MM patients with elevated CD229 expression achieved poor prognosis by analyzing MM clinical databases. In addition, CD229 promoted MM cell proliferation in vitro as well as in xenograft mouse model in vivo. Mechanism study revealed that CD229 promoted MM cell proliferation by regulating the RAS/ERK signaling pathway. Further exploration employed co-immunoprecipitation coupled with mass spectrometry to identify RASAL3 as an important downstream protein of CD229. Additionally, we developed a co-culture method combined with the immunofluorescence assay to confirm that intercellular tyrosine phosphorylation mediated self-activation of CD229 to activate RAS/ERK signaling pathway via interacting with RASAL3. Taken together, these findings not only demonstrate the oncogenic role of CD229 in MM cell proliferation, but also illustrate the potential of CD229 as a promising therapeutic target for MM treatment.