LDOC1 (leucine zipper, down-regulated in cancer 1)

LDOC1 (leucine zipper, down-regulated in cancer 1) is expressed by a wide variety of normal human tissues but is downregulated in various kinds of human cancers. Epigenetic silencing by promoter hypermethylation was shown to be an important cause of LDOC1 down-regulation in oral, cervical and ovarian cancers. The normal physiological function of LDOC1 is still not clear. But the ability of LDOC1 to induce apoptosis in various kinds of human cancer cells suggests this gene may act as a tumor suppressor

Reciprocal regulation of MicroRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells

BACKGROUND: MicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%. METHODS: The expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors. RESULTS: We observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3′UTR of IGF1R mRNA into the 3′UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3′UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling. CONCLUSION: Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation

Endogenous latent membrane protein 1 in Epstein–Barr virus-infected nasopharyngeal carcinoma cells attracts T lymphocytes through upregulation of multiple chemokines

AbstractTumor-infiltrating T lymphocytes are considered to facilitate development of Epstein–Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), but how EBV in NPC tumor cells directs T cell infiltration remains unclear. Here we compare EBV-infected NPC cells with and without spontaneous expression of viral latent membrane protein 1 (LMP1) and find that culture supernatants of LMP1-positive NPC cells exert enhanced chemoattraction to primary T cells. Knockdown of endogenous LMP1 in the cells suppresses the chemotactic activity. Endogenous LMP1 in NPC cells upregulates multiple chemokines, among which MIP-1α, MIP-1β and IL-8 contribute to T cell chemotaxis. We further reveal that LMP1-induced production of MIP-1α and MIP-1β in NPC cells requires not only two carboxyl-terminal activation regions of LMP1 but also their downstream NF-κB and JNK pathways. This study corroborates that endogenous LMP1 in EBV-infected NPC cells induces multiple chemokines to promote T cell recruitment and perhaps other pathogenic events in NPC

TNF-α-induced miR-450a mediates TMEM182 expression to promote oral squamous cell carcinoma motility.

Distant metastasis leads oral cancer patients into a poor survival rate and a high recurrence stage. During tumor progression, dysregulated microRNAs (miRNAs) have been reported to involve tumor initiation and modulate oral cancer malignancy. MiR-450a was significantly upregulated in oral squamous cell carcinoma (OSCC) patients without functional reports. This study was attempted to uncover the molecular mechanism of novel miR-450a in OSCC. Mir-450a expression was examined by quantitative RT-PCR, both in OSCC cell lines and patients. Specific target of miR-450a was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-450a and TMEM182 were accessed by adhesion and transwell invasion analyses. Determination of the expression and cellular localization of TMEM182 was examined by RT-PCR and by immunofluorescence staining. The signaling pathways involved in regulation of miR-450a were investigated using the kinase inhibitors. Overexpression of miR-450a in OSCC cells impaired cell adhesion ability and induced invasiveness, which demonstrated the functional role of miR-450a as an onco-miRNA. Interestingly, tumor necrosis factor alpha (TNF-α)-mediated expression of TMEM182 was regulated by miR-450a induction. MiR-450a-reduced cellular adhesion was abolished by TMEM182 restoration. Furthermore, the oncogenic activity of TNF-α/miR-450a/TMEM182 axis was primarily through activating extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. ERK1/2 inhibitor prevented the TNF-α-induced miR-450a expression and enhanced adhesion ability. Our data suggested that TNF-α-induced ERK1/2-dependent miR-450a against TMEM182 expression exerted a great influence on increasing OSCC motility. Overall, our results provide novel molecular insights into how TNF-α contributes to oral carcinogenesis through miR-450a that targets TMEM182

Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer

The discoidin domain receptor-1 (DDR1) is a non-integrin collagen receptor recently implicated in the collective cell migration of other cancer types. Previously, we identified an elevated expression of DDR1 in oral squamous cell carcinoma (OSCC) cells. Through the data mining of a microarray dataset composed of matched tumor-normal tissues from forty OSCC patients, we distilled overexpressed genes statistically associated with angiolymphatic invasion, including DDR1, COL4A5, COL4A6 and PDPN. Dual immunohistochemical staining further confirmed the spatial locations of DDR1 and PDPN in OSCC tissues indicative of collective cancer cell invasion. An elevated DDR1 expression at both the transcription and protein level was observed by treating keratinocytes with collagen of fibrillar or basement membrane types. In addition, inhibition of DDR1 kinase activity in OSCC TW2.6 cells disrupted cell cohesiveness in a 2D culture, reduced spheroid invasion in a collagen gel matrix, and suppressed angiolymphatic invasion in xenograft tissues. Taken together, these results suggest that collagen deposition in the affected tissues followed by DDR1 overexpression could be central to OSCC tumor growth and angiolymphatic invasion. Thus, DDR1 inhibitors are potential therapeutic compounds in restraining oral cancer, which has not been previously explored

Impact of Alcohol and Smoking on Outcomes of HPV-Related Oropharyngeal Cancer

Background: The aim of this study was to evaluate the impact of adverse lifestyle factors on outcomes in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Methods: From 2010 to 2019, 150 consecutive non-metastatic OPSCC patients receiving curative treatment in our institution were retrospectively enrolled. HPV positivity was defined as p16 expression ≥75%. The effects of adverse lifestyle factors on overall survival (OS) and disease-free survival (DFS) on OPSCC patients were determined. Results: The median follow-up duration was 3.6 years. Of the 150 OPSCCs, 51 (34%) patients were HPV-positive and 99 (66%) were HPV-negative. The adverse lifestyle exposure rates were 74.7% (n = 112) alcohol use, 57.3% (n = 86) betel grid chewing, and 78% (n = 117) cigarette smoking. Alcohol use strongly interacted with HPV positivity (HR, 6.00; 95% CI, 1.03–35.01), leading to an average 26.1% increased risk of disease relapse in patients with HPV-positive OPSCC. Heavy smoking age ≥30 pack-years was associated with increased risk of death (HR, 2.05; 95% CI, 1.05–4.00) and disease relapse (HR, 1.99; 95% CI, 1.06–3.75) in OPSCC patients. In stratified analyses, the 3-year absolute risk of disease relapse in HPV-positive OPSCC patients reached up to 50% when alcohol use and heavy smoking for ≥30 pack-years were combined. Conclusions: Alcohol acted as a significant treatment-effect modifier for DFS in HPV-positive OPSCC patients, diluting the favorable prognostic effect of HPV positivity. Heavy smoking age ≥30 pack-years was an independent adverse prognostic factor of OS and DFS in OPSCC patients. De-intensification treatment for HPV-related OPSCC may be avoided when these adverse lifestyle factors are present

Cost effectiveness of cancer treatment in Taiwan

This study aims to examine the cost effectiveness of treating major cancers compared with other major illnesses in Taiwan. Methods: We collected data on 395,330 patients with cancer, 125,277 patients with end-stage renal disease, and 50,481 patients under prolonged mechanical ventilation during 1998–2007. They were followed for 10–13 years to estimate lifetime survival functions using a semiparametric method. EuroQol five-dimension was used to measure the quality of life for 6189 cancer patients and 1401 patients with other illnesses. The mean utility values and healthcare costs reimbursed by the National Health Insurance were multiplied with the corresponding survival probabilities to estimate quality-adjusted life expectancies and lifetime costs, respectively. Data of 22,344 cancer patients under hospice care (considered as a comparison group) were used to conduct a cost-effectiveness analysis. Sensitivity analysis was conducted by assuming patients without treatment survived for 2 years with a quality of life value of 0.5. Results: The costs of care for patients under prolonged mechanical ventilation and those with end-stage renal disease were US$41,780–53,708 per quality-adjusted life year (QALY) and US$18,222–18,465 per QALY, respectively, which are equivalent to 2.17–2.79 gross domestic product (GDP) per capita per QALY and 1.18–1.25 GDP per capita per QALY. The costs of care for the nine different cancers were less than 1 GDP per capita per QALY, with those of lung, esophagus, and liver cancers being the highest. Sensitivity analysis showed the same conclusion. Lifetime risks of six out of nine cancer sites show an increased trend. Conclusion: Cancer care in Taiwan seemed cost effective compared with that of other illnesses, but prevention is necessary to make the National Health Insurance more sustainable

Healing the gap: the evolution of esophageal substitute and quality of life in patients undergoing total pharyngolaryngoesophagectomy with reconstruction

Aim: Hypopharyngeal squamous cell carcinoma is reportedly one of the most aggressive primary cancers, and surgical resection continues to be the standard therapeutic choice. In patients with hypopharyngeal cancer involving the esophagus or synchronous hypopharyngeal and esophageal cancer, total pharyngolaryngoesophagectomy (TPLE) is indicated to control both malignancies at the same time. Reconstruction remains challenging with regard to the length of the substitute for the esophagus as well as the donor site morbidity. We reported our long-term follow-up and the outcome of the quality of life (QoL).Methods: We retrospectively reviewed the records of all patients who underwent TPLE between January 2012 and December 2020. Information was collected on sex, age, surgical indications, operative time, postoperative complication, swallowing function, hospital stay, and survival. Quality of life scores were acquired by World Health Organization Quality of Life-Brief (WHOQOL-BREF) questionnaires and completed at the outpatient clinic. Gaussian kernel-smoothing was applied to estimate the dynamic changes of QoL function.Results: A total of 40 patients undergoing oncologic pharyngolaryngoesophagectomy were enrolled in this study. There were 26 patients (65%) undergoing gastric tube reconstruction with direct anastomosis to the oropharynx (GP group), 7 patients (18%) undergoing additional free jejunal flap to bridge the gap between the gastric tube and oropharynx (GP-JF group), 4 patients (10%) undergoing additional free anterolateral thigh flap to bridge the gap and resurface the neck skin (GP-ALT group), and 3 patients (8%) undergoing colon interposition (CI group). The leakage rate in each group was 50% for GP group, 29% for GP-JF group, 50% for GAP-ALT group, and 67% for CI group. The mean operation time was 1010 ± 195 min. Although the overall leakage rate was 47.5%, only 15% of the patients needed further surgical intervention. One patient (2.5%) died with persistent leakage and pneumonia. In terms of life quality assessment, the response rate for the QoL questionnaire was 50%. We found the overall QoL deteriorated for the first year after operation, but it gradually improved and even surpassed the patient pretreatment scores by the end of the second year after operation.Conclusion: The gap caused by TPLE in patient, perioperative morbidity, and postoperative quality of life could be managed by the evolution of esophageal substitute, surgical techniques, perioperative wound care, and evaluation of the quality of life

Evaluation of Objective and Subjective Swallowing Outcomes in Patients with Dysphagia Treated for Head and Neck Cancer

We evaluated objective and subjective swallowing function outcomes in patients with dysphagia treated for head and neck cancer (HNC) and identified risk factors for poor swallowing outcomes. Patients undergoing videofluoroscopic swallowing studies (VFSS) between January 2016 and March 2021 were divided into four groups according to primary tumor sites; post-treatment dysphagia was assessed. The penetration–aspiration scale (PAS) and bolus residue scale (BRS) were used to objectively assess swallowing function through VFSS. The Functional Oral Intake Scale (FOIS) was used for subjective analyses of swallowing statuses. To account for potential confounding, important covariates were adjusted for in logistic regression models. Oropharyngeal tumors were significantly more likely to have poor PAS and BRS scores than oral cavity tumors, and the patients with nasopharyngeal tumors were significantly less likely to have poor FOIS scores. Old age, having multiple HNCs, and a history of radiotherapy were associated with an increased odds of poor PAS scores (for all types of swallows), poor BRS scores (for semiliquid and solid swallows), and poor FOIS scores, respectively. This indicates using only subjective assessments may not allow for accurate evaluations of swallowing function in patients treated for HNC. Using both objective and subjective assessments may allow for comprehensive evaluations