Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear. METHODS AND MATERIALS: In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V). RESULTS: The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V. CONCLUSION: Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

Imaging considerations for salvage surgery in nasopharyngeal carcinoma: what surgeons need to know.

Nasopharyngeal carcinoma is frequently an undifferentiated squamous cell carcinoma, which is primarily treated with radiotherapy with or without chemotherapy; however, for residual or recurrent cancer, salvage surgery is the treatment of choice for resectable disease because it reduces the significant morbidity associated with re-irradiation. This review highlights the current surgical approach, mapping the extent of disease with an emphasis on magnetic resonance imaging (MRI) and integrated positron-emission tomography (PET)/computed tomography (CT), imaging features that determine operability for nasopharyngectomy and neck dissection, and need for a succinct radiological report and multidisciplinary team discussion, which are of paramount importance for successful surgical planning.

Early Detection of Cancer: Evaluation of MR Imaging Grading Systems in Patients with Suspected Nasopharyngeal Carcinoma.

BACKGROUND AND PURPOSE: We evaluated modifications to our contrast-enhanced MR imaging grading system for symptomatic patients with suspected nasopharyngeal carcinoma, aimed at improving discrimination of early-stage cancer and benign hyperplasia. We evaluated a second non-contrast-enhanced MR imaging grading system for asymptomatic patients from nasopharyngeal carcinoma plasma screening programs. MATERIALS AND METHODS: Dedicated nasopharyngeal MR imaging before (plain scan system) and after intravenous contrast administration (current and modified systems) was reviewed in patients from a nasopharyngeal carcinoma-endemic region, comprising 383 patients with suspected disease without nasopharyngeal carcinoma and 383 patients with nasopharyngeal carcinoma. The modified and plain scan systems refined primary tumor criteria, added a nodal assessment, and expanded the system from 4 to 5 grades. The overall combined sensitivity and specificity of the 3 systems were compared using the extended McNemar test (a χ2 value [Formula: see text]> 5.99 indicates significance). RESULTS: The current, modified, and plain scan MR imaging systems yielded sensitivities of 99.74%, 97.91%, and 97.65%, respectively, and specificities of 63.45%, 89.56% and 86.42%, respectively. The modified system yielded significantly better performance than the current ([Formula: see text] = 122) and plain scan ([Formula: see text] = 6.1) systems. The percentages of patients with nasopharyngeal carcinoma in grades 1-2, grade 3, and grades 4-5 for the modified and plain scan MR imaging systems were 0.42% and 0.44%; 6.31% and 6.96%; and 90.36% and 87.79%, respectively. No additional cancers were detected after contrast administration in cases of a plain scan graded 1-2. CONCLUSIONS: We propose a modified MR imaging grading system that improves diagnostic performance for nasopharyngeal carcinoma detection. Contrast was not valuable for low MR imaging grades, and the plain scan shows potential for use in screening programs.

MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia.

BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the χ2 test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.

Magnetic resonance imaging for the detection of nasopharyngeal carcinoma.

BACKGROUND: Endoscopic guided biopsy (EGB) is performed after an initial endoscopy for the investigation of patients with suspected nasopharyngeal carcinoma (NPC). The aim of the study was to determine whether MR imaging has the potential to replace invasive EGB in patients with a normal endoscopy. PATIENTS AND METHODS: Data from 2 groups of patients was reviewed, group 1 with proved NPC for MR staging (n = 456) and group 2 with suspected NPC (n = 77). The sensitivity was calculated for group 1 and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for group 2. RESULTS: In group 1, which included 118 of 456 (26%) with stage 1 disease, cancer was detected in all patients, giving a sensitivity of 100%. In group 2, MR imaging was negative for NPC in 70 (91%) patients, and no cancer has been detected on follow-up (follow-up range, 1-90 months; mean, 36 months). MR imaging was positive for NPC in 7 (9%) patients and NPC was confirmed by biopsy in 3 (4%). Two of these 3 patients had undergone negative endoscopy and biopsy before the MR imaging. NPC was not present in the remaining 4 patients, 2 of whom were found to have lymphoid hyperplasia. MR imaging had a sensitivity of 100%, specificity of 95%, NPV of 100%, PPV of 43%, and accuracy of 95%. CONCLUSION: MR imaging has the potential to screen healthy patients who do not require EGB and direct the site of biopsy in small cancers that may be missed by endoscopy. On the basis of these results, a prospective study is planned.

Detection of Nasopharyngeal Carcinoma by MR Imaging: Diagnostic Accuracy of MRI Compared with Endoscopy and Endoscopic Biopsy Based on Long-Term Follow-Up.

BACKGROUND AND PURPOSE: Our previous nasopharyngeal carcinoma detection study, comparing MR imaging, endoscopy, and endoscopic biopsy, showed that MR imaging is a highly sensitive test that identifies nasopharyngeal carcinomas missed by endoscopy. However, at the close of that study, patients without biopsy-proved nasopharyngeal carcinoma nevertheless had shown suspicious abnormalities on endoscopy and/or MR imaging. The aim of this study was to determine whether there were any patients with undiagnosed nasopharyngeal carcinoma by obtaining long-term follow-up and to use these data to re-evaluate the diagnostic performance of MR imaging. MATERIALS AND METHODS: In the previous study, 246 patients referred to a hospital ear, nose, and throat clinic with suspected nasopharyngeal carcinoma, based on a wide range of clinical indications, had undergone MR imaging, endoscopy, and endoscopic biopsy, and 77 had biopsy-proved nasopharyngeal carcinoma. One hundred twenty-six of 169 patients without biopsy-proved nasopharyngeal carcinoma underwent re-examination of the nasopharynx after a minimum of 3 years, including 17 patients in whom a previous examination (MR imaging = 11; endoscopy = 7) had been positive for nasopharyngeal carcinoma, but the biopsy had been negative for it. Patients with nasopharyngeal carcinoma were identified by biopsy obtained in the previous and this follow-up study; patients without nasopharyngeal carcinoma were identified by the absence of a tumor on re-examination of the nasopharynx. The sensitivity and specificity of the previous investigations were updated and compared by using the Fisher exact test. RESULTS: One patient with a previous positive MR imaging finding was subsequently proved to have nasopharyngeal carcinoma. Nasopharyngeal carcinomas were not found in the remaining 125 patients at follow-up, and the previous positive findings for nasopharyngeal carcinoma on MR imaging and endoscopy were attributed to benign lymphoid hyperplasia. The diagnostic performances for the previous MR imaging, endoscopy, and endoscopic biopsy were 100%, 88%, and 94%, respectively, for sensitivity, and 92%, 94%, and 100%, respectively, for specificity; the differences between MR imaging and endoscopy were significant for sensitivity (P = .003) but not specificity (P = .617). CONCLUSIONS: MR imaging detected the 12% of nasopharyngeal carcinomas that were endoscopically invisible, including 1 cancer that remained endoscopically occult for several years. Lymphoid hyperplasia reduced the specificity of MR imaging.

Resistance to apoptosis of HPV 16-infected laryngeal cancer cells is associated with decreased Bak and increased Bcl-2 expression.

Human papillomavirus type 16 (HPV 16) plays an etiological role in human laryngeal carcinoma. Apoptosis is closely associated with various biological processes including oncogenesis. This study investigated how HPV 16 oncoproteins E6 and E7 affect apoptosis in human laryngeal cancer cells. We established two human laryngeal cancer cell lines that expressed HPV 16 E6 and E7, respectively. Using these two cell lines, we found that both E6 and E7 exhibited an inhibitive effect on apoptosis induced by tumor necrosis factor alpha and cycloheximide. In both transfected cell lines, the expression of pro-apoptotic Bak was reduced and that of anti-apoptotic Bcl-2 was over-expressed. However, the expression of caspase-3 and caspase-8 was not significantly different between the E6- and E7-transfected cells and the control cells without HPV 16. p53 Protein was not detected in either the transfected or the non-transfected cells. Our study indicates that: (1) HPV 16 E6 and E7 oncoproteins are capable of inhibiting apoptosis in laryngeal squamous carcinoma cells; (2) the mechanism modulated by E6 and E7 involves the over-expression of Bcl-2 and the down-regulation of Bak; (3) the anti-apoptotic pathway is not related to the level of p53, caspase-3, or caspase-8. These results suggest that the dysregulation of apoptotic molecules Bak and Bcl-2 by HPV 16 E6 and E7 plays a role in the prolongation of cell survival, which may subsequently contribute to the development of human laryngeal cancer.

A surgical technique to prevent tracheostomal stenosis after laryngectomy.

Tracheostomal stenosis after total laryngectomy is a frequently occurring nuisance to both the patient and the surgeon. Although many causes may contribute to the development of tracheostomal stenosis, operative technique seems to play a major role. The authors describe and explain their method of stomal construction. Over a 10-year period they have used the described method on 260 patients undergoing a total laryngectomy, with an incidence of tracheostomal stenosis of 6%.

Clinical signs of orbital ischemia in rhino-orbitocerebral mucormycosis.

Mucormycosis is the most acutely fatal fungus infection of man (Ferry and Abedi). The most common clinical type of infection is rhino-orbitocerebral mucormycosis. Prompt recognition of the clinical picture is essential if the appropriate urgent management is to be instituted without delay. The presence of black eschar in the region of the nasal passages, palate, midface, and orbit is the best-recognized clinical sign alerting the clinician to the diagnosis. Black eschar is, however, a feature in only a minority of these patients at the time of presentation. This paper discusses other clinical signs, particularly orbital ischemia, which should suggest the diagnosis. The clinical presentation of orbital ischemia in mucormycosis includes proptosis, total external and internal ophthalmoplegia, and early blindness. A lax, nontender periorbital puffiness, which does not feel warm to the examiner's touch, is typical. Proptosis and chemosis, if present, are mild. These signs are compared with those of pyogenic orbital cellulitis, with which the condition might most easily be confused.

Bilateral parotid and submandibular gland enlargement: rare features of Wegener's granulomatosis.

Wegener's granulomatosis is a potentially fatal disease of unknown origin affecting mainly the upper and lower respiratory tracts and kidneys. Prompt recognition of the more unusual presentations of the disease is necessary to ensure early treatment. We present a case of a 46-year-old female with bilateral submandibular and parotid gland enlargement. Parotid or submandibular salivary gland enlargement is a rare presenting feature of Wegener's granulomatosis. Common to 80 per cent of these cases is nasal involvement, while ear pathology or lung lesions may occur in the remaining cases. The diagnosis is both clinical and pathological, biopsy of suspicious tissue, serum c-ANCA levels and a chest X-ray are valuable investigations. Treatment with immunosuppressive therapy is essential, and usually ensures a long-term remission.

Conversion from a non-indwelling to a Provox2 indwelling voice prosthesis for speech rehabilitation: comparison of voice quality and patient preference.

This prospective study assessed the advantages and problems associated with converting a patient using an older generation non-indwelling voice prosthesis to a newer generation indwelling voice prosthesis, in this case the Provox2. The voice characteristics of each patient were measured using the old and then the new voice prosthesis. Technical aspects of the insertion of the indwelling prosthesis were noted. Each patient completed a questionnaire after a period of use with the indwelling prosthesis. Changing the prosthesis was simple and uncomplicated in 15 of 17 patients. Acoustic analysis showed improved parameters with the indwelling prosthesis, but no perceptual difference between the two prostheses. The questionnaire revealed that most patients preferred the indwelling prosthesis. Replacing a non-indwelling with an indwelling prosthesis is technically simple, leading to improvement in voice quality and patient satisfaction. It may be reasonable to offer this choice to patients currently using an older generation non-indwelling voice prosthesis.

T2-weighted MR imaging early after chemoradiotherapy to evaluate treatment response in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: T2-weighted MRI shows potential in early posttreatment assessment of the primary tumor. Residual masses composed entirely of low T2-signal scar tissue suggest local control and those ≥1 cm of similar signal to untreated tumor suggest local failure. The purpose of this study was to investigate the diagnostic accuracy of T2-weighted MR imaging early after chemoradiotherapy for identifying primary tumor treatment failure in squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: At 6 weeks after treatment, T2-weighted MR images of 37 primary tumors in 37 patients were assessed. Residual masses were divided into 3 patterns: pattern 1 = scar tissue only (flat-edged/retracted mass of low T2 signal intensity); pattern 2 = mass without features described in pattern 1 or 3; and pattern 3 = any pattern that included an expansile mass ≥1 cm of intermediate T2 signal intensity (similar grade of signal intensity to the untreated tumor). T2 patterns were analyzed for local outcome (Fisher exact test) and time to local failure (univariate and multivariate analysis of T2 pattern, age, T stage, and tumor size by use of the Cox regression model). RESULTS: Residual masses after treatment were present in 34 (92%) of 37 patients. Local failures occurred in residual masses with pattern 1 in 0 (0%) of 14 patients; pattern 2 in 6 (55%) of 11 patients; and pattern 3 in 9 (100%) of 9 patients. Significant associations were found between local control and pattern 1 (P = <.0001; sensitivity, 74%; specificity, 100%; PPV, 100%; NPV, 75%; accuracy, 85%), and between local failure and pattern 3 (P = <.0001; sensitivity, 60%; specificity, 100%; PPV, 100%; NPV, 76%; accuracy, 82%). Pattern 2 showed no significant associations with local outcome. Univariate analysis of time to local failure showed that the T2 pattern was significant (P < .0001) and remained significant on multivariate analysis. CONCLUSIONS: T2-weighted MR imaging is a potential tool for early posttreatment assessment of primary HNSCC treatment response. Awareness of correlation of the T2 pattern of any residual mass with treatment outcome at the primary site may contribute to patient treatment.

Aspergillus pachymeningitis mimicking nasopharyngeal carcinoma.

OBJECTIVES: We report a case of otogenic fungal pachymeningitis in a diabetic patient who presented with multiple cranial nerve palsies and nasopharyngeal swelling. METHODS: We present a case report, we describe the investigations, management and clinical course of fungal pachymeningitis, and we present a review of the world literature on fungal and non-fungal pachymeningitis. RESULTS: To our knowledge, this is the first report of fungal pachymeningitis with magnetic resonance imaging features suggestive of nasopharyngeal carcinoma. It is also the first reported case with aspergillus cultured from both a dural biopsy and the ear canal. CONCLUSION: Fungal pachymeningitis is a rare condition which may present to otorhinolaryngologists. Its clinical and radiological findings can be confused with those of nasopharyngeal carcinoma; fungal pachymeningitis should thus be included in the differential diagnosis of nasopharyngeal carcinoma.

Can diffusion-weighted imaging distinguish between normal and squamous cell carcinoma of the palatine tonsil?

The utility of diffusion-weighted imaging (DWI) in the detection of squamous cell carcinoma (SCC) of the tonsils has not been previously investigated. This preliminary study compared DWI of apparent SCC tonsillar tumours with normal tonsils. DWI of the tonsils was performed in 10 patients with newly diagnosed tonsil SCC that was evident on conventional MRI and in 17 patients undergoing cranial MRI for other indications. Regions of interest (ROI) were drawn around each identifiable tonsil on the apparent diffusion coefficient (ADC) map and the mean ADC value for each tonsil was calculated. ADC values for normal and SCC tonsils were compared using the Mann-Whitney U-test. The median ADC and range (x10(-3) mm(2) s(-1)) were found to be 0.814 and 0.548-1.312, respectively, for normal tonsils compared with 0.933 and 0.789-1.175, respectively, for SCC tonsils. ADC values were significantly higher for SCC tonsils than for normal tonsils (p = 0.009). No SCC tonsil had an ADC less than 0.82 x 10(-3) mm(2) s(-1) compared with 58% of normal tonsils. We conclude that there is a difference in the ADC between normal tonsils and SCC tonsils where the cancer is apparent on conventional MRI. These results are promising, although further studies are now required to determine whether DWI can be used to identify or exclude smaller foci of SCC within tonsils where the cancer is not evident on conventional MRI.

Does primary tumour volumetry performed early in the course of definitive concomitant chemoradiotherapy for head and neck squamous cell carcinoma improve prediction of primary site outcome?

Although previous studies have documented correlations between pre-treatment or post-treatment primary tumour volumes and local outcome following definitive concomitant chemoradiotherapy (CCRT) in head and neck squamous cell carcinoma (HNSCC), no study has included and compared tumour volumes during CCRT. We reviewed the MRIs of 69 HNSCC patients treated with a 6 weeks course of CCRT and who underwent successful MRI pre-treatment (n = 69), 2 weeks intra-treatment (n = 48) and 6 weeks post-treatment (n = 61). Primary tumour volumes on MRI at the three time points were calculated and compared for their predictive value for primary site outcome. Volume thresholds optimised to predict failure with the highest accuracy and positive predictive value (PPV) were calculated. The mean pre-treatment volume was 24.6 cm³ (range, 1.1-187.9 cm³) and the mean follow-up interval was 41 months (range, 12-100 months). 23 primary tumours failed treatment (33%). Volumes before, during and after CCRT were positively associated with local failure (p = 0.015, p = 0.009, p<0.0001). Volume reductions during and after CCRT were negatively associated with local failure (p = 0.021, p = 0.001). Pre-treatment and intra-treatment volume thresholds achieved the highest accuracy and produced intermediate PPVs (51-64%) for predicting local failure. Optimised intra-treatment thresholds did not identify any more treatment failures than the pre-treatment thresholds. By comparison, a 6 weeks post-treatment volume reduction (<35%) achieved 100% PPV for failure, albeit with 26% sensitivity. In conclusion, primary tumour volumetry performed early in CCRT provides minimal additional information compared with pre-treatment volumetry, with respect to predicting post-treatment local failures. Therefore, volumetry during CCRT is unlikely to be useful for guiding individual response-based therapeutic modifications.

Quality of life in head and neck cancer patients after surgical resection: translation into Cantonese and validation of the EORTC QLQ-H&N35.

CONCLUSION: High convergent and discriminant validity between subscales was achieved after the translation of EORTC QLQ-H&N35 into Cantonese. Most subscales were assessing distinct components of quality of life (QoL). OBJECTIVES: The study aimed to translate the EORTC QLQ-H&N35 cancer module into Cantonese and to confirm validity and reliability for use in a Hong Kong head and neck (H&N) cancer population. SUBJECTS AND METHODS: An ethnocentric forward-backward translation of EORTC QLQ-H&N35 was conducted by bilingual head and neck health professionals. Discrepancies were identified and problematic wording and concepts revised. Further review preceded pilot testing in 119 postoperative H&N cancer patients. Internal consistency within each subscale, convergent and discriminant validity to check the item relevance and item representativeness within and between subscales were examined. Mean and standard deviations of each subscale and single item and Cronbach's alpha coefficients for subscales were calculated. RESULTS: Six of seven subscales achieved standard reliability (Cronbach's alpha coefficient >0.7). Correlation coefficients between an item and its own subscale were significantly higher than the coefficients with other subscales. Scaling success was found in all subscales. Pearson's correlation coefficient between subscales was <0.70, except between the subscales swallowing and trouble with social eating (r = 0.795), and speech problems and social contact (r = 0.754).

'Steam-boat' supraglottic laryngoplasty for treatment of chronic refractory aspiration: a modification of Biller's technique.

OBJECTIVE: The surgical treatment of intractable aspiration usually requires sacrifice of the patient's natural voice to prevent food entering the airway. Biller described a tubed supraglottic laryngoplasty to control aspiration while allowing patients to phonate with their larynx. Our preliminary experience with this technique in Chinese patients has been disappointing, as tension in the mucosa on wound closure led to wound dehiscence. Our objective was to modify Biller's technique in order to achieve a better outcome. METHOD: We modified Biller's technique by trimming the epiglottic cartilage and by inserting a tibial periosteal graft to reinforce closure of the mucosa, creating an arrangement resembling a Chinese steam boat. RESULTS: Three Chinese patients underwent the modified Biller's technique. No wound dehiscence occurred, the surgery controlled aspiration, and the patients were able to phonate with their own larynx. All patients resumed oral feeding, and previously placed gastrostomy tubes were removed. CONCLUSION: The 'steam-boat' supraglottic laryngoplasty is a viable surgical alternative to total laryngectomy or tracheal diversion for controlling intractable aspiration, and preserves a phonating larynx.

Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor-ERK pathway.

OBJECTIVES: Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17beta-oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. MATERIALS AND METHODS: Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) alpha and beta were regulated by their agonists (PPT and DPN), antagonists and siRNA. RESULTS: E2 promoted cell proliferation. Such an effect was positively related to ERalpha but negatively to ERbeta; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl-2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2-induced cell proliferation. Knockdown of ERalpha significantly attenuated E2-mediated Bcl-2 and pERK1/2 expression. In contrast, knockdown of ERbeta markedly enhanced them. CONCLUSIONS: Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl-2 and decrease in Bax levels in an ERK1/2-related pathway. Imbalance between ERalpha and ERbeta may contribute to thyroid carcinogenesis.

Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells.

The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.