Transmembrane Protease, Serine 3 Research Articles

TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation

BackgroundIt is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated...

Upregulation of the transmembrane protease serine 3mRNA level in radioresistant colorectal cancer tissues.

Aim: To investigate the clinical role of transmembrane protease serine 3 (TMPRSS3) in radioresistance and prognosis of colorectal cancer (CRC). Methods: Standardized mean difference (SMD) and summary area under the curve (AUC) of TMPRSS3 were calculated by combining all available high-throughput data globally. The prognostic significance of TMPRSS3 was determined by Kaplan-Meier and Cox regression analyses. Results:TMPRSS3 was remarkably upregulated in 198 CRC radioresistant cases compared with nonradioresistance (SMD=0.38, AUC=0.71). Overexpression of TMPRSS3 was observed in 1601 CRC patientscompared with control subjects without CRC. TMPRSS3 was a risk factor for disease-free survival of CRC with the summarized hazard ratio 1.28. Conclusion: TMPRSS3 contributes to the radioresistance and unfavorable prognosis of CRC.

Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss.

A previous study indicated that mutations in the transmembrane protease serine 3 (TMPRSS3) gene, which encodes a transmembrane serine protease, cause nonsyndromic hearing loss (NSHL). This was the first description of a serine protease involved in hearing loss (HL). In Taiwan, however, data on the TMPRSS3 gene’s association with NSHL is still insufficient. In this study, we described 10 mutations of TMPRSS3 genes found in 14 patients after screening 230 children with NSHL. The prevalence of the TMPRSS3 mutation appeared to be 6.09% (14/230). Of the 10 mutations, three were missense mutations: c.239G>A (p.R80H), c.551T>C (p.L184S), and 1253C>T (p.A418V); three were silent mutations, and four were mutations in introns. To determine the functional importance of TMPRSS3 mutations, we constructed plasmids carrying TMPRSS3 mutations of p.R80H, p.L184S, and p.A418V. TMPRSS3 function can be examined by secretory genetic assay for site-specific proteolysis (sGASP) and Xenopus oocyte expression system. Our results showed that p.R80H, p.L184S, and p.A418V TMPRSS3 mutations gave ratios of 19.4%, 13.2%, and 27.6%, respectively, via the sGASP system. Moreover, these three TMPRSS3 mutations failed to activate the epithelial sodium channel (ENaC) in the Xenopus oocyte expression system. These results indicate that the p.R80H, p.L184S, and p.A418V missense mutations of TMPRSS3 resulted in greatly diminishing the proteolytic activity of TMPRSS3. Our study provides information for understanding the importance of TMPRSS3 in the NSHL of Taiwanese children and provides a novel molecular explanation for the role of TMPRSS3 in HL.

Long non‑coding RNA EBLN3P promotes the recovery of the function of impaired spiral ganglion neurons by competitively binding to miR‑204‑5p and regulating TMPRSS3 expression

Sensorineural hearing loss (SNHL) is one of the major leading causes of hearing impairment, and is typically characterized by the degeneration of spiral ganglion neurons (SGNs). In previous studies by the authors, it was demonstrated that microRNA (miRNA or miR)-204-5p decreased the viability of SGNs by inhibiting the expression of transmembrane protease, serine 3 (TMPRSS3), which was closely associated with the development of SGNs. However, the upstream regulatory mechanism of miR-204-5p was not fully elucidated. The present study found that an important upstream regulatory factor of miR-204-5p, long non-coding RNA (lncRNA) EBLN3P, was expressed at low levels in impaired SGNs, whereas it was expressed at high levels in normal SGNs. Mechanistic analyses demonstrated that lncRNA EBLN3P functioned as a competing endogenous RNA (ceRNA) when regulating miR-204-5p in normal SGNs. In addition, lncRNA EBLN3P regulated TMPRSS3 expression via the regulation of miR-204-5p in normal SGNs. In vitro functional analysis revealed that lncRNA EBLN3P promoted the recovery of the viability of normal SGNs and inhibited the apoptosis of normal SGNs. Finally, the results revealed a recovery-promoting effect of lncRNA EBLN3P on the structure and function of impaired SGNs in models of deafness. On the whole, the findings of the present study demonstrate that lncRNA EBLN3P promotes the recovery of the function of impaired SGNs by competitively binding to miR-204-5p and regulating TMPRSS3 expression. This suggests that lncRNA EBLN3P may be a potential therapeutic target for diseases involving SNHL.

TMPRSS3 regulates cell viability and apoptosis processes of HEI-OC1 cells via regulation of the circ-Slc4a2, miR-182 and Akt cascade.

The present study aimed to investigate the functions and regulation mechanism of the transmembrane protease, serine 3 (TMPRSS3), which plays an important role in sensorineural hearing loss. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, comprising auditory-related cells, were used in the present study. An overexpression vector and small hairpin RNA target on TMPRSS3 were designed and transfected into HEI-OC1 cells. Circular RNA (circRNA) sequencing was conducted and expression profiles were obtained. The circular structure of circRNAs was validated with a polymerase chain reaction and Sanger sequencing using convergent and divergent primers. Overexpression of TMPRSS3 increased cell viability, whereas suppression of TMPRSS3 increased the percentage of apoptotic cells and decreased cell viability, compared to the control group. circRNA sequencing provided expression profiles indicating that the overexpression of TMPRSS3 increased the expression level of 195 circRNAs. Results of GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) studies indicated that the circRNAs are focused on the RAS signaling pathway. The pathway, circ-Slc41a2 (chr10: 82744115|82767120), miR-182 and Akt, might comprise one of the key cascades of TMPRSS3. TMPRSS3 is an important molecule in the regulation of cell viability and cell apoptosis of HEI-OC1 cells. Its functions are dependent on the circ-Slc41a2, miR-182 and Akt cascade.

Knockdown of TMPRSS3 inhibits cell proliferation, migration/invasion and induces apoptosis of glioma cells.

Transmembrane protease serine 3 (TMPRSS3) is a member of type II transmembrane serine proteases (TTSP) family, which play important roles in the development and progression of various cancers. However, the role of TMPRSS3 in glioma remains unclear. In the present study, we evaluated the expression patterns of TMPRSS3 in clinical tumor samples and glioma cell lines. The results showed that TMPRSS3 was highly expressed in both human glioma tissues and cell lines. Knockdown of TMPRSS3 in glioma cells by transfection with small interfering RNA targeting TMPRSS3 (si-TMPRSS3) significantly suppressed cell proliferation and migration/invasion. Moreover, knockdown of TMPRSS3 markedly elevated the apoptotic rate of glioma cells. Si-TMPRSS3 transfection also resulted in a remarkable increase in bax expression and a notable decrease in bcl-2 expression in glioma cells. Furthermore, TMPRSS3 knockdown markedly suppressed the expressions of Notch1 and Hes1. The results indicated that knockdown of TMPRSS3 exhibited antiglioma effect, which is associated with the inactivation of the Notch signaling pathway. These findings suggested that TMPRSS3 might be used as a therapeutic target for glioma treatment.

Knockdown of TMPRSS3 inhibits gastric cancer cell proliferation, invasion and EMT via regulation of the ERK1/2 and PI3K/Akt pathways

The transmembrane protease, serine 3 (TMPRSS3), a member of the type II transmembrane serine protease family, plays an important role in mediating tissue development, homeostasis and various biological processes. Recently, TMPRSS3 has been reported to be involved in cancer progression. However, the role of TMPRSS3 in gastric cancer (GC) remains largely unknown. In this study, we found that TMPRSS3 was highly expressed in GC tissues and cell lines. Knockdown of TMPRSS3 inhibited GC cell proliferation, invasion and epithelial-mesenchymal transition (EMT) in vitro as well as suppressed GC cell growth and dissemination in vivo. These inhibitory effects were mediated by regulation of the ERK1/2 signaling pathway. Moreover, TMPRSS3-mediated ERK1/2 activation was dependent on the PI3K/Akt pathway. In conclusion, TMPRSS3 contributed to GC progression via activation of the PI3K/Akt/ERK signaling pathway and might act as a therapeutic target for GC treatment.

TMPRSS3 modulates ovarian cancer cell proliferation, invasion and metastasis.

Overexpression of transmembrane protease, serine 3 (TMPRSS3) has been detected in ovarian cancer. However, the molecular mechanisms of TMPRSS3 in ovarian cancer remain unclear. In the present study, we found that TMPRSS3 was significantly expressed in ovarian cancer cells. Overexpression of TMPRSS3 promoted the proliferation, invasion and migration of A2780 cells. Conversely, knockdown of TMPRSS3 in HO8910 cells inhibited the proliferation, invasion and migration. Furthermore, TMPRSS3 affected the expression levels of E-cadherin, vimentin and Twist. In addition, TMPRSS3 induced activation of ERK1/2 in ovarian cancer cells, and the ERK1/2 pathway was required for the TMPRSS3-mediated proliferation, invasion and migration of ovarian cancer cells. Finally, knockdown of TMPRSS3 inhibited ovarian cancer HO8910 cell growth and metastasis in vivo. Collectively, the present study suggests that TMPRSS3 plays a crucial role in the development and progression of ovarian cancer. Therefore, TMPRSS3 represents a potential therapeutic target of ovarian cancer.

MiR-204 suppresses cochlear spiral ganglion neuron survival in vitro by targeting TMPRSS3

Sensorineural hearing loss (SNHL) is the most common cause of hearing impairment. One of the essential steps to prevent progressive hearing loss is to protect spiral ganglion neurons (SGNs) from ongoing degeneration. MicroRNAs and TMPRSS3 (transmembrane protease, serine 3) have been reported to be involved in development of SGNs and genesis of SNHL. The aim of this study was to investigate the role of miR-204 and TMPRSS3 in SGNs. Effect of miR-204 on cell viability of SGNs was first examined using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Expression of TMPRSS3 in SGNs with or without addition of miR-204 was assessed by real-time PCR and western blot further. A luciferase reporter activity assay was conducted to confirm target association between miR-204 and 3′-UTR of TMPRSS3. Finally, role of TMPRSS3 on cell viability of SGNs was evaluated by transfection of TMPRSS3 siRNA. Cell viability of SGNs was suppressed by miR-204 in a concentration-dependent manner. Overexpression of miR-204 reduced expression of TMPRSS3 in SGNs at both mRNA and protein levels. Binding to the 3′-UTR of TMPRSS3 by miR-204 was identified by luciferase assay. Knockdown of TMPRSS3 by siRNA significantly inhibits cell viability of SGNs. miR-204 could be a potential therapeutic target in sensorineural hearing loss.

Expression of TMPRSS3 in the rat cochlea following kanamycin ototoxicity

To establish the kanamycin-induced deafness model in SD rats, and to investigate the expression and significance of transmembrane protease, serine 3 (TMPRSS3) in the cochlea following kanamycin ototoxicity. A total of 40 male SD rats were randomly divided into 4 groups. The experimental rats received intramuscular kanamycin sulfate for 3, 7, and 14 consecutive days, and the control group were treated with normal saline for 14 days. Auditory brainstem responses (ABR) were obtained before and after the kanamycin administration. The expression of TMPRSS3 in the cochlea was identified and detected by immunohistochemistry and Western blot. Kanamycin-induced deafness model in the SD rats was successfully established. ABR thresholds were increased and the expression of TMPRSS3 in the cochlea was reduced after the kanamycin injection (P<0.01). TMPRSS3 may play an important role in normal cochlea function and involve in the process of aminoglycoside antibiotics induced deafness.

Expression of proteinase TMPRSS3 in mouse cochlea

To observe the expression of proteinase transmembrane protease, serine 3 (TMPRSS3) in mouse cochlea, and to investigate the significance of TMPRSS3 in the inner ear. The protein expression of TMPRSS3 in C57/BL mouse cochlea was identified and detected by immunohistochemistry and immunofluorescence. Different cochlear tissues, such as spiral ganglion neurons, corti organ, stria vascularis and so on, were separated to detect the gene expression of TMPRSS3 by real-time fluorescence quantitative polymerase chain reaction (qPCR). The cochlear tissues with different ages were collected and the expression of TMPRSS3 mRNA was detected by qPCR. TMPRSS3 was mainly expressed in the spiral ganglion neurons, and there was TMPRSS3 mRNA in the cochlea in groups with different age. The expression level of TMPRSS3 mRNA was much weaker. The distribution of TMPRSS3 was observed in many regions of the mouse cochlea, but mainly in the spiral ganglion neurons. This indicates that TMPRSS3 may be involved in the physiological functional regulation of the spiral ganglion neurons.

TMPRSS3 (transmembrane protease, serine 3)

Review on TMPRSS3 (transmembrane protease, serine 3), with data on DNA, on the protein encoded, and where the gene is implicated.

Coexistence of Unverricht‐Lundborg disease and congenital deafness: Molecular resolution of a complex comorbidity

We report on genetic analysis of a complex condition in a Serbian family of four siblings, wherein two had progressive myoclonic epilepsy (PME) and congenital deafness (CD), one had isolated congenital deafness (ICD), and one was healthy. Molecular diagnosis performed by Southern blotting confirmed Unverricht-Lundborg disease in the available sibling with PME/CD. In the sibling with ICD (heterozygote for expansion mutation in CSTB) we demonstrated recombination event between the D21S2040 marker and the CSTB gene and identified c.207delC (p.T70Xfs) mutation in the fourth exon of the transmembrane protease, serine-3 (TMPRSS3) gene (maps in close proximity to CSTB), responsible for nonsyndromic deafness in the sibling with PME/CD as well. To the best of our knowledge this is the first genetic confirmation of the coexistence of these two mutations.