Contactin-1 (CNTN1), a neuronal cell adhesion molecular, functions in nervous system development and has been associated with carcinogenesis and tumor progression. To investigate the role of CNTN1 in gefitinib resistance in lung adenocarcinoma, lentivirus-mediated short hairpin (sh)RNA was used to silence CNTN1 and its physiological function was analyzed in the A549 cell line. A cell cytotoxicity assay revealed that CNTN1 knockdown enhanced gefitinib sensitivity in the A549 cells. In addition, CNTN1 knockdown, together with gefitinib treatment, resulted in a significant inhibition of colony formation and migration, and promotion of apoptosis. Furthermore, CNTN1 knockdown also reversed the epithelial-mesenchymal transition (EMT) phenotype by increasing E-cadherin protein expression level, and decreasing N-cadherin and vimentin protein expression levels. The PI3K/Akt signaling pathway was also association with the effects of CNTN1 on EMT progression and gefitinib resistance in the A549 cells. Collectively, knockdown of CNTN1 reversed the EMT phenotype and enhanced gefitinib sensitivity in the A549 cells by inhibiting the activation of the PI3K/Akt signaling pathway. These results suggested that CNTN1 may represent a potential therapeutic target for reserving EGFR-tyrosine kinase inhibitor resistance in non-small cell lung cancer.

• Akt
• CNTN1
• epithelial-mesenchymal transition
• gefitinib
• resistance

Contactin 1 (CNTN1) is a new oncogenic protein of prostate cancer (PC); its impact on PC remains incompletely understood. We observed CNTN1 upregulation in LNCaP cell-derived castration-resistant PCs (CRPC) and CNTN1-mediated enhancement of LNCaP cell proliferation. CNTN1 overexpression in LNCaP cells resulted in enrichment of the CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_3 gene set that facilitates endocrine resistance in breast cancer. The leading-edge (LE) genes (n = 10) of this enrichment consist of four genes with limited knowledge on PC and six genes novel to PC. These LE genes display differential expression during PC initiation, metastatic progression, and CRPC development, and they predict PC relapse following curative therapies at hazard ratio (HR) 2.72, 95% confidence interval (CI) 1.96–3.77, and p = 1.77 × 10⁻⁹ in The Cancer Genome Atlas (TCGA) PanCancer cohort (n = 492) and HR 2.72, 95% CI 1.84–4.01, and p = 4.99 × 10⁻⁷ in Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 140). The LE gene panel classifies high-, moderate-, and low-risk of PC relapse in both cohorts. Additionally, the gene panel robustly predicts poor overall survival in clear cell renal cell carcinoma (ccRCC, p = 1.13 × 10⁻¹¹), consistent with ccRCC and PC both being urogenital cancers. Collectively, we report multiple CNTN1-related genes relevant to PC and their biomarker values in predicting PC relapse.

• Contactin 1
• biomarkers
• prostate cancer
• prostate cancer recurrence

• PI3K/Akt
• chemoresistance
• contactin-1
• docetaxel
• epithelial-mesenchymal transition
• prostate cancer

Cancers are among the difficult-to-treat diseases despite advances in diagnosis and treatment. Although newer effective targets remain to be discovered, targeted therapy has emerged as a promising field. In the last decade, contactin 1 (CNTN1) has surfaced as an important cancer-related molecule. CNTN1 is a neuronal membrane glycoprotein, which, if overexpressed, is found in different cancer cell lines, cancer tissues, and transgenic mice. It is positively associated with lymphatic invasion, metastasis, late TNM stage, and a short overall survival time. However, the role of CNTN1 in cancer cell proliferation remains unclear. In addition, CNTN1 is involved in cancer cell invasion, migration, metastasis, and chemoresistance by promoting epithelial-mesenchymal transition and mediating several signal transduction pathways. Several studies suggest CNTN1 as a new therapeutic target for cancers. This review aims to summarize the research developments on CNTN1 in various cancers, to establish its role in epithelial-mesenchymal transition and signal transduction pathways, and to identify promising areas for further investigation.

• PI3K/AKT
• cancers
• contactin 1 (CNTN1)
• epithelial-mesenchymal transition (EMT)
• signal transduction pathways
• targeted therapy

• Contactin 1 (CNTN1)
• cancer progression
• metastasis
• tumorigenesis

• Animals
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Contactin 1/genetics
• Contactin 1/metabolism
• Humans
• Neurogenesis
• Oncogene Proteins/genetics
• Oncogene Proteins/metabolism
• Signal Transduction

• CIHR

Distinguishing between different types of thyroid cancers (TC) remains challenging in clinical laboratories. As different tumor types require different clinical interventions, it is necessary to establish new methods for accurate diagnosis of TC.

Proteomic analysis of the human serum was performed through data-independent acquisition mass spectrometry for 29 patients with TC (stages I–IV): 13 cases of papillary TC (PTC), 10 cases of medullary TC (MTC), and six cases follicular TC (FTC). In addition, 15 patients with benign thyroid nodules (TNs) and 10 healthy controls (HCs) were included in this study. Subsequently, 17 differentially expressed proteins were identified in 291 patients with TC, including 247 with PTC, 38 with MTC, and six with FTC, and 69 patients with benign TNs and 176 with HC, using enzyme-linked immunosorbent assays.

In total, 517 proteins were detected in the serum samples using an Orbitrap Q-Exactive-plus mass spectrometer. The amyloid beta A4 protein, apolipoprotein A-IV, gelsolin, contactin-1, gamma-glutamyl hydrolase, and complement factor H-related protein 1 (CFHR1) were selected for further analysis. The median serum CFHR1 levels were significantly higher in the MTC and FTC groups than in the PTC and control groups (P < 0.001). CFHR1 exhibited higher diagnostic performance in distinguishing patients with MTC from those with PTC (P < 0.001), with a sensitivity of 100.0%, specificity of 85.08%, area under the curve of 0.93, and detection cut-off of 0.92 ng/mL.

CFHR1 may serve as a novel biomarker to distinguish PTC from MTC with high sensitivity and specificity.

• Biomarker
• Complement factor H-related protein 1
• Diagnosis
• Proteomics
• Serum
• Thyroid cancer

Contactin-1 (CNTN-1) has been reported to serve an oncogenic role in several cancer types. However, detailed mechanisms describing the influence of CNTN-1 in prostate cancer progression have not yet been elucidated. The present study aimed to determine the clinical significance of CNTN-1 expression in prostate cancer progression, and also to investigate the regulatory role of CNTN-1 in the proliferation, migration and invasive ability of prostate cancer cells. The results of the present study indicated that expression levels of CNTN-1 were significantly higher in prostate cancer tissues compared with adjacent normal tissues. Moreover, a high expression level of CNTN-1 was positively correlated with tumor size, stage and metastasis, as well as a poorer prognosis in patients with prostate cancer. Furthermore, CNTN-1-knockdown in prostate cancer cells (using short hairpin RNA) resulted in the significant inhibition of cancer cell proliferation, colony formation, migration and invasiveness. Silencing of CNTN-1 expression also suppressed epithelial-mesenchymal transition in prostate cancer cells via the upregulation of E-cadherin, and the downregulation of N-cadherin and vimentin expression. Inhibition of CNTN-1 expression also reduced the activity of the PI3K/AKT signaling pathway in prostate cancer cells. Thus, it was demonstrated that CNTN-1 expression is upregulated, and plays an oncogenic role, in prostate cancer cells. The results of the current study suggest that CNTN-1 may represent a promising therapeutic target, potentially improving the treatment of patients with prostate cancer.

• contactin-1
• invasion
• migration
• proliferation
• prostate cancer

• Flt-4
• VEGF-C
• autocrine manner
• contactin-1
• metastasis
• migration
• oral squamous cell carcinoma
• proliferation
• tumor cell

Contactin1 (CNTN1) has been shown to play an important role in the invasion and metastasis of several tumors; however, the role of CNTN1 in breast cancer has not been fully studied. The purpose of this study is to investigate the role of CNTN1 in regulating tumor growth, migration and invasion in breast cancer.

To investigate its function, CNTN1 was expressed in Hs578T cells. CNTN1 expression was confirmed by western blot, immunohistochemistry and real-time RT-PCR. The effect of CNTN1 overexpression on proliferation, migration and invasion of Hs578T breast cancer cells was assessed in vitro and in vivo. Our results showed that CNTN1 overexpression promoted Hs578T cell proliferation, cell cycle progression, colony formation, invasion and migration. Notably, overexpression of CNTN1 in Hs578T cells enhanced the growth of mouse xenograft tumors.

CNTN1 promotes growth, metastasis and invasion of Hs578T breast cancer cell line. Thus, therapies targeting CNTN1 may prove efficacious for breast cancer. However, further investigation is required to understand the mechanism by which CNTN1 influences proliferation, metastasis and invasion in breast cancer.

The online version of this article (10.1186/s12860-018-0154-3) contains supplementary material, which is available to authorized users.

• Breast cancer
• CNTN1
• Hs578T
• Invasion
• Migration
• Proliferation

Paraneoplastic neurological syndromes (PNS) are rare neurological disorders in which ectopic expression of neural antigens by a tumor results in an autoimmune attack against the nervous system. Onconeural antibodies not only guide PNS diagnosis but may also help detecting underlying malignancies. Our project aims to uncover new potential antibodies in paraneoplastic neuropathies (PN).

Thirty‐four patients fulfilling diagnostic criteria of possible (n = 9; 26.5%) and definite (n = 25; 73.5%) PN without onconeural antibodies and 28 healthy controls were included in our study. Sera were tested for known antibodies against neural cell adhesion molecules and screened for novel IgG and IgM reactivities against nerve components: dorsal root ganglia (DRG) neurons, motor neurons, and Schwann cells. Patients showing autoantibodies against any of these cell types were used for immunoprecipitation (IP) studies.

Overall, 9 (26.5%) patients showed significant reactivity against DRG neurons, motor neurons, or Schwann cells, whereas 5 (17.9%) healthy controls only showed moderate reactivity. Compared with control sera, serum samples from patients with paraneoplastic sensory‐motor neuropathies had a higher frequency of IgM antibodies against Schwann cells (0% vs. 40%; P = 0.0028). No novel antigens were identified from our IP experiments. Antibodies against the neural adhesion molecules CNTN1, NF155, NF140, NF186, NCAM1, L1CAM, and the CNTN1/CASPR1 complex were not detected in patients with PN. One (2.9%) patient with CIDP and thymoma had CASPR2 antibodies.

Almost 30% of patients with PN harbor antibodies targeting neural structures, suggesting that novel neoplasm‐associated antigens remain to be discovered.

• apoptosis
• liver regeneration
• obstructive jaundice
• simvastatin
• transforming growth factor-β1 signaling pathway

CNTN1, a member of the CNTN family of neural cell-recognition molecules, is involved in tumor invasion and metastasis. Although the expression of CNTN1 has been reported in several human malignancies, the expression of CNTN1 in hepatocellular carcinoma (HCC) and its correlation with prognosis remain unclear. The aim of this study was to evaluate the expression of CNTN1 and determine the clinicopathological parameters and prognostic value of CNTN1 in HCC patients.

Quantitative real-time polymerase chain-reaction and Western blotting assays were performed to assess messenger RNA and protein levels of CNTN1 in 20 matched HCC specimens. The clinical and prognostic significance of CNTN1 in 90 cases of HCC was determined by immunohistochemistry.

CNTN1 expression was higher in HCC compared to the expression found in adjacent tissues at both messenger RNA and protein levels (P<0.01). Notably, immunohistochemical results revealed that CNTN1 expression was significantly higher in HCC compared to adjacent tissues (54.4% vs 12.2%, P=0.01). Furthermore, positive CNTN1 expression was associated with tumor size, tumor capsulae, status of metastasis, and tumor–node–metastasis stage. Kaplan–Meier survival analysis showed that high CNTN1 was correlated with reduced overall survival (OS) rate (P<0.001) and disease-free survival (DFS) rate (P=0.001). Multivariate analysis identified CNTN1 as an independent poor prognostic factor of OS and DFS in HCC patients (P=0.007 and P=0.002, respectively).

Our results suggest that CNTN1 could play an important role in HCC and serve as an independent unfavorable prognostic factor for OS and DFS and a potential therapeutic target for HCC.

• CNTN1
• expression
• hepatocellular carcinoma
• immunohis-tochemistry
• prognosis

The neural cell adhesion molecule contactin-1 (CNTN1), first identified as a member of the contactin subpopulation of the immunoglobulin superfamily, is associated with many other cell surface proteins expressed on a variety of neurocytes, contributing to their functions and maturation. It has been recently found that the abnormal expression of CNTN1 has a close correlation with tumor initiation, development, invasiveness, metastasis and prognosis. The acquired metastatic ability of malignant tumors is caused by a population of cancer cells with the capacities of invasiveness, metastasis, adherence and proliferation, in which abnormal gene expression may play an important role. This review focuses on the current advances in research of CNTN1 in the nerve system, and mainly in the malignant tumors, with an aim to provide new clues to clinical prevention, diagnosis and treatment of these malignancies.

• Contactin-1
• Neoplasm
• Targeted therapy

• RET
• Thyroid cancer
• biomarker
• contactin 1
• metastasis
• rearrangement

• Biomarkers, Tumor/analysis
• Blotting, Western
• Cell Proliferation/physiology
• Contactin 1/metabolism
• Gene Expression Regulation, Neoplastic/physiology
• Gene Knockdown Techniques
• Gene Rearrangement
• Humans
• Immunohistochemistry
• Neoplasm Invasiveness/genetics
• Neoplasm Invasiveness/pathology
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-ret/genetics
• RNA, Small Interfering
• Real-Time Polymerase Chain Reaction
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/pathology
• Transfection

Despite advances in diagnosis and treatment, gastric cancer remains one of the most common malignant tumors worldwide, and early diagnosis remains a challenge. The lack of effective methods to detect these tumors early is a major factor contributing to the high mortality in patients with gastric cancer, who are typically diagnosed at an advanced stage. Additionally, the early detection of metastases and the curative treatment of gastric cancer are difficult to achieve, and the detailed mechanisms remain to be fully elucidated. Thus, the identification of valuable predictive biomarkers and therapeutic targets to improve the prognosis of patients with gastric cancer is becoming increasingly important. Contactin 1 (CNTN1), a cell adhesion molecule, is a glycosylphosphatidylinositol-anchored neuronal membrane protein that plays an important role in cancer progression. The expression of CNTN1 is upregulated in primary lesions, and its expression level correlates with tumor metastasis in cancer patients. The current evidence reveals that the functions of CNTN1 in the development and progression of cancer likely promote the invasion and metastasis of cancer cells via the VEGFC/FLT4 axis, the RHOA-dependent pathway, the Notch signaling pathway and the epithelial-mesenchymal transition progression. Therefore, CNTN1 may be a novel biomarker and a possible therapeutic target in cancer treatment in the near future.

• Cancer/neoplasms
• Stomach
• Contactin 1
• Metastasis
• Molecular target

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/metabolism
• Contactin 1/antagonists & inhibitors
• Contactin 1/metabolism
• Disease Progression
• Humans
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Predictive Value of Tests
• Prognosis
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Up-Regulation

Contactin-1 has been shown to promote cancer metastasis. However, the underlying mechanisms remain unclear. We report here that knockdown of contactin-1 in A549 lung cancer cells reduced A549 cell invasion and the cell's ability to grow in soft agar without affecting cell proliferation. Reduction of contactin-1 resulted in upregulation of E-cadherin, consistent with E-cadherin being inhibitive of cancer cell invasion. In an effort to investigate the mechanisms whereby contactin-1 reduces E-cadherin expression, we observed that contactin-1 plays a role in AKT activation, as knockdown of contactin-1 attenuated AKT activation. Additionally, inhibition of AKT activation significantly enhanced E-cadherin expression, an observation that mimics the situation observed in contactin-1 knockdown, suggesting that activation of AKT plays a role in contactin-1-mediated downregulation of E-cadherin. In addition, we were able to show that knockdown of contactin-1 did not further reduce A549 cell's invasion ability, when AKT activation was inhibited by an AKT inhibitor. To further support our findings, we overexpressed CNTN-1 in two CNTN-1 null breast cancer cell lines expressing E-cadherin. Upon overexpression, CNTN-1 reduced E-cadherin levels in one cell line and increased AKT activation in the other. Furthermore, in our study of 63 primary lung cancers, we observed 65% of primary lung cancers being contactin-1 positive and in these carcinomas, 61% were E-cadherin negative. Collectively, we provide evidence that contactin-1 plays a role in the downregulation of E-cadherin in lung cancer and that AKT activation contributes to this process. In a study of mechanisms responsible for contactin-1 to activate AKT, we demonstrated that knockdown of CNTN-1 in A549 cells did not enhance PTEN expression but upregulated PHLPP2, a phosphatase that dephosphorylates AKT. These observations thus suggest that contactin-1 enhances AKT activation in part by preventing PHLPP2-mediated AKT dephosphrorylation.

• Adult
• Aged
• Antigens, CD
• Cadherins/metabolism
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Cell Line, Tumor
• Cell Proliferation
• Contactin 1/metabolism
• Disease Progression
• Down-Regulation
• Enzyme Activation
• Female
• Humans
• Lung Neoplasms/enzymology
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Metastasis
• Phosphoprotein Phosphatases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Tissue Array Analysis
• Up-Regulation