POLM variant G312R promotes ovarian tumorigenesis through genomic instability and COL11A1-NF-κB axis.

In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA polymerase mu (POLM), especially G312R mutation, in propelling oncogenesis through dual pathways. POLMG312R markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. In addition, our research reveals that POLMG312R perturbs collagen alpha-1 (XI) chain (COL11A1) expression-a gene that plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression.NEW & NOTEWORTHY Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLMG312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLMG312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.

Analysis of cancer-associated fibroblasts related genes identifies COL11A1 associated with lung adenocarcinoma prognosis.

BACKGROUND: The treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma. METHODS: The Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated. RESULTS: Using the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma. CONCLUSION: COL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.

COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation.

Machine learning (ML) algorithms were used to identify a novel biological target for breast cancer and explored its relationship with the tumor microenvironment (TME) and patient prognosis. The edgR package identified hub genes associated with overall survival (OS) and prognosis, which were validated using public datasets. Of 149 up-regulated genes identified in tumor tissues, three ML algorithms identified COL11A1 as a hub gene. COL11A1was highly expressed in breast cancer samples and associated with a poor prognosis, and positively correlated with a stromal score (r=0.49, p<0.001) and the ESTIMATE score (r=0.29, p<0.001) in the TME. Furthermore, COL11A1 negatively correlated with B cells, CD4 and CD8 cells, but positively associated with cancer-associated fibroblasts. Forty-three related immune-regulation genes associated with COL11A1 were identified, and a five-gene immune regulation signature was built. Compared with clinical factors, this gene signature was an independent risk factor for prognosis (HR=2.591, 95%CI 1.831-3.668, p=7.7e-08). A nomogram combining the gene signature with clinical variables, showed better predictive performance (C-index=0.776). The model correction prediction curve showed little bias from the ideal curve. COL11A1 is a potential therapeutic target in breast cancer and may be involved in the tumor immune infiltration; its high expression is strongly associated with poor prognosis.

MiR-4458-loaded gelatin nanospheres target COL11A1 for DDR2/SRC signaling pathway inactivation to suppress the progression of estrogen receptor-positive breast cancer.

RNA interference is a promising way to treat cancer and the construction of a stable drug delivery system is critically important for its application. Gelatin nanospheres (GNs) comprise a biodegradable drug vehicle with excellent biocompatibility, but there are limited studies on its delivery and role in the stabilization of miRNA and siRNA. Breast cancer is the most diagnosed type of female cancer worldwide. Abnormal miRNA expression is closely related to the occurrence and progression of estrogen receptor-positive (ER+) breast cancer. In this study, miR-4458 was upregulated in ER+ breast cancer and could inhibit MCF-7 cell viability, colony formation, migration, and invasion. Collagen type XI alpha 1 (COL11A1) was identified as a directly interacting protein of miR-4458 and an important component of the extracellular matrix. High COL11A1 expression was positively correlated with poor prognosis, lower overall survival, disease-free survival, and a late tumor-node-metastasis stage. COL11A1 knockdown could inhibit MCF-7 cell migration and invasion. GNs were used to load a miR-4458 mimic or COL11A1 siRNA (si-COL11A1) to achieve sustained and controlled release in xenograft nude mice. Their tumor volume was decreased, tumor cell apoptosis was promoted, and hepatic metastasis was significantly inhibited. Moreover, the DDR2/SRC signaling pathway was inactivated after transfection with the miR-4458 mimic and si-COL11A1. In conclusion, GNs can be potentially used to deliver siRNA or miRNA, and miR-4458 and COL11A1 can be possible targets for ER+ breast cancer treatment.

An investigation on the c-MYC, AXIN1, and COL11A1 gene expression in colorectal cancer.

The high incidence rate of CRC demands early diagnosis of the disease and readiness of diagnostic biomarker. In present study, we have investigated c-MYC, AXIN1, and COL11A1 expression levels in course of CRC progression and their correlation with demographics and clinical risk factors. Fifty-five tumors and 41 normal tissues were obtained from Tumor Bank of Iran, total RNA was extracted, cDNA was synthesized, and RT-qPCR was performed. Results were analyzed using Rest 2009 and SPSS software. Analysis at mRNA level showed upregulation of the two genes; c-MYC with a p-value of 0.001 and COL11A1 with an observed p-value of 0.02, while a p-value of 0.04 indicated AXIN1 downregulation. The observed overexpression of COL11A1 in stage 0 compared to other stages of CRC asserts importance of this gene in CRC prognosis. Moreover, statistical analysis confirms a significant correlation between expression of these genes and several clinical risk factors of CRC. Our study supports the importance of the studied genes and provides further information regarding the molecular mechanism of CRC. Further studies on these genes could elucidate their pivotal role for both early detection and/or diagnosis of CRC in addition to have important biomarkers for CRC management available.

Collagen XI Alpha 1 (COL11A1) Expression in the Tumor Microenvironment Drives Neuroblastoma Dissemination.

BACKGROUND: Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination particularly cancer associated fibroblast (CAFs). CAFs synthesise the extracellular matrix to create a scaffold for tumor growth thus enabling the carcinogenesis of NB, Collagen, an abundant scaffold protein produced by CAFs, has been implicated in the creation of an optimal tumor microenvironment, however, the expression profile of collagen within NB is not yet known. METHODS: We characterised collagen expression within the tumor-stroma boundary by microarray and confirmed by qRT-PCR and immunohistochemistry. RESULTS: The collagen marker, COL11A1, was also upregulated in NB CD45+ cells and SMA+ CAFs. Furthermore, SMA+ CAFs led to neuroblastoma cell invasion in an in vitro co-culture system which was subsequently attenuated by gene silencing COL11A1. Immunohistochemical staining of clinical tumor samples revealed that high COL11A1 expression in the stroma adjacent to tumour site, significantly associated with advanced cancer stages, age ≥18 months, undifferentiated tumor status, relapse and poor overall survival. CONCLUSION: Collectively, these results suggest that a COL11A1 signature in the NB microenvironment could represent a novel target for therapeutic intervention.

Mutually Exclusive Expression of COL11A1 by CAFs and Tumour Cells in a Large panCancer and a Salivary Gland Carcinoma Cohort.

Procollagen 11A1 (COL11A1) is a central component of the extracellular matrix in many carcinomas, which is considered to be mainly produced by cancer associated fibroblasts (CAFs). As COL11A1 expression correlates with adverse prognosis and is implicated in chemoresistance, it is a promising putative target. For the first time, we used RNA in-situ hybridization to systematically identify the cells that produce COL11A1 in the ten most prevalent carcinoma types, lymphomas (n = 275) and corresponding normal tissue (n = 55; panCancer cohort). Moreover, as most salivary gland carcinomas (SGC) display distinct stromal architectures, we also analysed 110 SGC. The corresponding protein formation of COL11A1 was determined by MALDI-TOF-MS-Imaging. We report that colon, breast and salivary duct carcinomas are highly infiltrated by COL11A1 positive CAFs (CAFsCOL11A1) and might thus be promising candidates for antidesmoplastic or COL11A1-targeted therapies. The amount of CAFsCOL11A1 correlated significantly with tumour grade, tumour stage and nodal spread in the panCancer cohort. Significant associations between CAFsCOL11A1 and vascular invasion, perineural spread and nodal spread were observed in the SGC cohort. Also, we discovered that tumour cells of intercalated duct derived SGC and CAFs produce COL11A1 in a mutually exclusive manner. Our findings represent a novel mode of extracellular matrix production in carcinomas and could be highly relevant in the future. Our findings elucidate the mode of COL11A1 expression in very different carcinoma types and may aid to categorise tumours in the setting of possible future COL11A1-related therapies.

Hearing Outcomes in Stickler Syndrome: Variation Due to COL2A1 and COL11A1.

OBJECTIVES: Stickler syndrome (SS) is a heterogeneous inherited connective tissue disorder, often due to a mutation in COL2A1 or COL11A1. Mutations in these genes cause collagen abnormalities affecting ocular, auditory, orofacial, and skeletal systems, including hearing loss, micrognathia, and cleft palate. Understanding the variability of hearing phenotypes based on genetic mutation has a significant impact on treatment and long-term care. DESIGN: A retrospective chart review of pediatric patients with a confirmed diagnosis of SS between January 2003 and December 2018 at a tertiary pediatric hospital was performed. Patients were excluded if they did not have genetic evaluation, craniofacial/ear, nose, and throat evaluation, and/or audiologic testing. Charts were reviewed for the following information: age, race, sex, SS diagnosis, genetic variant of SS, and audiological testing data. RESULTS: There were 29 confirmed patients with SS who met criteria, 16 with type I (COL2A1) and 13 with type II (COL11A1). Of the 13 patients with type II, 12 (92%) demonstrated hearing loss, ranging in severity from mild to severe. In type I, 25% of patients had mild or resolved hearing loss. CONCLUSION: Results suggest that patients with type II SS are more likely to have congenital hearing loss than type I. Data also suggest that the COL11A1 mutation shows consistently more severe hearing loss than the COL2A1 mutation.

Mutant collagen COL11A1 enhances cancerous invasion.

Collagens are the most abundant proteins in the body and comprise the basement membranes and stroma through which cancerous invasion occurs; however, a pro-neoplastic function for mutant collagens is undefined. Here we identify COL11A1 mutations in 66 of 100 cutaneous squamous cell carcinomas (cSCCs), the second most common U.S. cancer, concentrated in a triple helical region known to produce trans-dominant collagens. Analysis of COL11A1 and other collagen genes found that they are mutated across common epithelial malignancies. Knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo. Compared to otherwise genetically identical COL11A1 wild-type tissue, gene-edited mutant COL11A1 skin is characterized by induction of ß1 integrin targets and accelerated neoplastic invasion. In mosaic tissue, mutant COL11A1 cells enhanced invasion by neighboring wild-type cells. These results suggest that specific collagens are commonly mutated in cancer and that mutant collagens may accelerate this process.

Single-cell analysis reveals the pan-cancer invasiveness-associated transition of adipose-derived stromal cells into COL11A1-expressing cancer-associated fibroblasts.

During the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with poor prognosis, invasiveness, metastasis and resistance to therapy in multiple cancer types, characterized by a gene expression signature with prominent presence of genes COL11A1, THBS2 and INHBA. Identifying the underlying biological mechanisms responsible for their creation may facilitate the discovery of targets for potential pan-cancer therapeutics. Using a novel computational approach for single-cell gene expression data analysis identifying the dominant cell populations in a sequence of samples from patients at various stages, we conclude that these fibroblasts are produced by a pan-cancer cellular transition originating from a particular type of adipose-derived stromal cells naturally present in the stromal vascular fraction of normal adipose tissue, having a characteristic gene expression signature. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profiles of cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transition. These results also provide an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression.

Circ-0005105 activates COL11A1 by targeting miR-20a-3p to promote pancreatic ductal adenocarcinoma progression.

Growing evidence indicates that circular RNAs (circRNAs) are closely involved in tumorigenesis, but the association between circRNAs and pancreatic ductal adenocarcinoma (PDAC) is far from clear. Here, we focused on the functional investigation of circ-0005105, a newly identified circRNA, in PDAC progression. In the present study, we assessed circ-0005105 expression in PDAC tissues and cell lines with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The biological functions of circ-0005105 in cellular proliferation and invasion were identified through gain- and loss-of-function experiments in vitro and in vivo. The interaction between circ-0005105 and the microRNA (miR)-20a-3p-COL11A1 (collagen type XI alpha 1) axis was examined using luciferase reporter and RNA immunoprecipitation assays. We found that circ-0005105 expression was upregulated in both PDAC tissues and cell lines. Higher circ-0005105 expression correlated positively with the malignant clinical phenotype and poor prognosis of patients with PDAC. Gain- and loss-of-function analysis showed that circ-0005105 facilitated both in vitro and in vivo cellular proliferation and invasion. Mechanistically, circ-000510 served as a competing endogenous RNA (ceRNA) of miR-20a-3p and indirectly modulated COL11A1 expression, leading to activation of epithelial-mesenchymal transition (EMT). Rescue experiments suggested that the oncogenic activity of circ-0005105 was dependent on the modulation of the miR-20a-3p-COL11A1 axis. More importantly, COL11A1 overexpression was significantly associated with poor prognosis in PDAC, and silencing COL11A1 reduced PDAC cell tumorigenicity and metastasis. Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p-COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.

Identification of core genes and clinical outcomes in tumors originated from endoderm (gastric cancer and lung carcinoma) via bioinformatics analysis.

ABSTRACT: During last decade, bioinformatics analysis has provided an effective way to study the relationship between various genes and biological processes. In this study, we aimed to identify potential core candidate genes and underlying mechanisms of progression of lung and gastric carcinomas which both originated from endoderm. The expression profiles, GSE54129 (gastric carcinoma) and GSE27262 (lung carcinoma), were collected from GEO database. One hundred eleven patients with gastric carcinoma and 21 health people were included in this research. Meanwhile, there were 25 lung carcinoma patients. Then, 75 differentially expressed genes were selected via GEO2R online tool and Venn software, including 31 up-regulated genes and 44 down-regulated genes. Next, we used Database for Annotation, Visualization, and Integrated Discovery and Metascpe software to analyze Kyoto Encyclopedia of Gene and Genome pathway and gene ontology. Furthermore, Cytoscape software and MCODE App were performed to construct complex of these differentially expressed genes . Twenty core genes were identified, which mainly enriched in extracellular matrix-receptor interaction, focal adhesion, and PI3K-Akt pathway (P < .01). Finally, the significant difference of gene expression between cancer tissues and normal tissues in both lung and gastric carcinomas was examined by Gene Expression Profiling Interactive Analysis database. Twelve candidate genes with positive statistical significance (P < .01), COMP CTHRC1 COL1A1 SPP1 COL11A1 COL10A1 CXCL13 CLDN3 CLDN1 matrix metalloproteinases 7 ADAM12 PLAU, were picked out to further analysis. The Kaplan-Meier plotter website was applied to examine relationship among these genes and clinical outcomes. We found 4 genes (ADAM12, SPP1, COL1A1, COL11A1) were significantly associated with poor prognosis in both lung and gastric carcinoma patients (P  < .05). In conclusion, these candidate genes may be potential therapeutic targets for cancer treatment.

A repeated triple lysine motif anchors complexes containing bone sialoprotein and the type XI collagen A1 chain involved in bone mineralization.

While details remain unclear, initiation of woven bone mineralization is believed to be mediated by collagen and potentially nucleated by bone sialoprotein (BSP). Interestingly, our recent publication showed that BSP and type XI collagen form complexes in mineralizing osteoblastic cultures. To learn more, we examined the protein composition of extracellular sites of de novo hydroxyapatite deposition which were enriched in BSP and Col11a1 containing an alternatively spliced "6b" exonal sequence. An alternate splice variant "6a" sequence was not similarly co-localized. BSP and Col11a1 co-purify upon ion-exchange chromatography or immunoprecipitation. Binding of the Col11a1 "6b" exonal sequence to bone sialoprotein was demonstrated with overlapping peptides. Peptide 3, containing three unique lysine-triplet sequences, displayed the greatest binding to osteoblastic cultures; peptides containing fewer lysine triplet motifs or derived from the "6a" exon yielded dramatically lower binding. Similar results were obtained with 6-carboxyfluorescein (FAM)-conjugated peptides and western blots containing extracts from osteoblastic cultures. Mass spectroscopic mapping demonstrated that FAM-peptide 3 bound to 90 kDa BSP and its 18 to 60 kDa fragments, as well as to 110 kDa nucleolin. In osteoblastic cultures, FAM-peptide 3 localized to biomineralization foci (site of BSP) and to nucleoli (site of nucleolin). In bone sections, biotin-labeled peptide 3 bound to sites of new bone formation which were co-labeled with anti-BSP antibodies. These results establish the fluorescent peptide 3 conjugate as the first nonantibody-based method to identify BSP on western blots and in/on cells. Further examination of the "6b" splice variant interactions will likely reveal new insights into bone mineralization during development.

Familial Short Stature-A Novel Phenotype of Growth Plate Collagenopathies.

CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤ -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

COL11A1 Was Involved in Cell Proliferation, Apoptosis and Migration in Non-Small Cell Lung Cancer Cells.

BACKGROUND: Type XI collagen (COL11A1) was reported to associate with malignancy in several cancer types, whereas its role in lung cancer is not fully understood. Therefore, the present study aimed to explore the expression level and biological role of COL11A1 in lung cancer cells. METHODS: Gene Expression Omnibus (GEO) database containing 6 lung cancer tissues and normal lung tissues was used to identify potential aberrantly expressed genes. The expression of COL11A1, apoptosis related genes, cell cycle related genes and migration associated genes at the protein level were evaluated by western blot and at the mRNA level was determined by real-time PCR in lung cancer cell lines. Furthermore, the expression of COL11A1 was silenced by siRNA, and cell viability was detected by Cell counting kit-8 (CCK-8) assay. Moreover, cell apoptosis and cell cycle were determined by flow cytometry. In addition, transwell and wound-healing assay were applied to determine cell migration ability. RESULTS: GEO analysis suggests that COL11A1 was highly expressed in patients with lung cancer, which was consistent with the results in lung cancer cell lines. COL11A1 knockdown in lung cancer cells significantly lowered the colony formation ability, augmented cell apoptosis rate and elevated the expression of cleaved caspase-3, cleaved caspase-9, Bax, P21 and the expression of Bcl-2, CyclinD1, CDK2 and CDK-4 was significantly downregulated (all p < 0.05). Moreover, post-COL11A1 knockdown, the cell wound-healing and migration ability was significantly impaired, which also supported by the upregulation of E-Cadherin and downregulation of N-Cadherin, Vimentin and Snail (all p < 0.05). Furthermore, we also found that COL11A1 knockdown decreased the expression of p-AKT, p-PI3K and p-ERK. CONCLUSION: The present study revealed that COL11A1 may contribute to the malignancy and involve in the pathogenesis of lung cancer.

Auditory dysfunction in type 2 Stickler Syndrome.

PURPOSE: To present the extent and site of lesion of auditory dysfunction in a large cohort of individuals with type 2 Stickler Syndrome. Type 2 Stickler Syndrome results from a mutation in the gene coding for α-1 type XI pro-collagen, which has been identified in the human vitreous, cartilage and the cochlea of the mouse. The condition is characterised by classic ocular abnormalities, auditory dysfunction, osteoarthropathy and oro-facial dysplasia. METHODS: This is a population study which used a combination of audiometric, tympanometric, and self-report measures on a series of 65 individuals (mean age 29.2 years, range 3-70, female 63.1%) with genetically confirmed type 2 Stickler Syndrome. RESULTS: Hearing impairment was identified in at least one ear for 69% of individuals. Analysis against age-matched normative data showed that reduced hearing sensitivity was present across all test frequencies. Sensorineural hearing loss was most common (77% of ears), with conductive (3%), mixed (7%) and no hearing loss (13%), respectively. The proportion of hypermobile tympanic membranes (24%) was less than previously documented in type 1 Stickler Syndrome. When present, this appears to arise as a direct result of collagen abnormalities in the middle ear. Self-report measures of speech and spatial hearing in sound were comparable to a non-syndromic cohort with similar audiometric thresholds. CONCLUSIONS: Auditory impairment in type 2 Stickler Syndrome is predominantly associated with cochlear hearing loss of varying severities across affected individuals. The impact on hearing thresholds can be seen across the frequency range, suggesting a contribution of defective collagen throughout the cochlea. Self-report questionnaires showed that difficulties understanding speech, and spatial information in sound (such as that used for localisation), were worse than a young, normal-hearing population but comparable to a non-syndromic cohort with similar audiometric thresholds. Therefore, it is likely that hearing loss in type 2 Stickler Syndrome arises in the auditory periphery, without significant central processing deficits.

Integrated bioinformatics analysis identified COL11A1 as an immune infiltrates correlated prognosticator in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is the most common pancreatic cancer, with high mortality rate and limited treatment options. Tumor infiltrating cells and genes in microenvironment are emerging as pivotal players in PAAD progression and prognosis. In this study, we obtained genes expression data set GSE119794 of PAAD, which contains data from 10 tumor and 10 normal samples. A total of 262 differentially expressed genes (DEGs), including 169 up-regulated and 93 down-regulated genes, were obtained based on expression fold change and significance. Combining the pathway analysis of DEGs and GSEA analysis of all genes, four KEGG pathways were enriched. The 4 pathways include pancreatic secretion, protein digestion and absorption, fat digestion and absorption, and PPAR signaling pathways. Functional enrichment of Gene Ontology significantly enriched extracellular matrix, an important component in microenvironment. In the Protein-protein interaction (PPI) network, we screened out 3 hub genes of COL11A1, KRT19 and CXCL5 by CytoHubba. At last, the expression level, prognostic significance and correlation with tumor infiltrates were validated in TCGA database, with GEPIA and TIMER. The validation identified Collagen Type XI Alpha 1 Chain (COL11A1), an extracellular matrix structural constituent, as a hazardous prognosticator with significant correlation with macrophage, neutrophil and dendritic cells. In sum, we identified COL11A1 as an immune infiltrates correlated prognosticator in pancreatic adenocarcinoma.

Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia.

Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in COL11A1 (c.2241 + 5G>T, c.2809 - 2A>G, c.3168 + 5G>C) and COL11A2 (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative COL11A1 and COL11A2 transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of COL11-related disorders.