Utilizing Filipino key informants to guide community outreach for cancer prevention in Hawai'i.

OBJECTIVE/DESIGN: The University of Hawai'i Cancer Center works with academic and community partners to examine health disparities and inequities that persist among Pacific Island Populations through the Pacific Island Partnership for Cancer Health Equity (PIPCHE). The Partnership's Community Outreach Core (COC) assists and promotes cancer research and helps to ensure the integration of historically excluded community perspectives by utilizing community-engaged and culturally-grounded approaches to reduce cancer burdens. However, cancer health disparities among Filipinos demonstrate a need for cancer-control initiatives within this community. SAMPLE/MEASUREMENTS: COC staff conducted five semi-structured key informant interviews with Filipino nurse and healthcare leaders in Hawai'i to establishpartnerships with the community, as well as provide community-driven guidance for future cancer prevention and control efforts. RESULTS: The informants provided recommendations for COC community engagement, relationship building, and future areas of directed cancer focus. The interviews also initiated relationship-building and community collaborations for directed cancer education and resources within Filipino communities. CONCLUSION: The themes uncovered from the interviews provided guidance on how to begin addressing cancer concerns, and led to the informants' subsequent membership in our Outreach Advisory Council to engage in future collaboration with the Filipino community and a framework for future community-engaged cancer prevention efforts.

Evaluation of a brief harm reduction intervention to reduce celebratory drinking among college students.

Objectives: To assess the effectiveness of a harm reduction e-card at increasing protective drinking behaviors and decreasing negative outcomes from consuming alcohol.Participants: Participants were college students who turned 21 years old between January 21 2016 and September 27 2017. A total of 1,064 students completed the posttest: 737 from the experimental group and 327 from the control group.Methods: This study is a randomized controlled trial evaluation. Three days prior to their birthdays, students were randomly selected to receive a harm reduction e-card (experimental group) or not (control group). Three days after their birthdays, all students were sent an electronic posttest survey to the student's university email address.Results: Students who received the e-card intervention reported employing more protective behaviors than the individuals who did not receive the card. Conclusions: This evaluation concludes that a harm reduction e-card successfully increased the use of protective drinking strategies but did not impact negative outcomes.

The potential of using artificial intelligence to improve skin cancer diagnoses in Hawai'i's multiethnic population.

Skin cancer remains the most commonly diagnosed cancer in the USA with more than 1 million new cases each year. Melanomas account for about 1% of all skin cancers and most skin cancer deaths. Multiethnic individuals whose skin is pigmented underestimate their risk for skin cancers and melanomas and may delay seeking a diagnosis. The use of artificial intelligence may help improve the diagnostic precision of dermatologists/physicians to identify malignant lesions. To validate our artificial intelligence's efficiency in distinguishing between images, we utilized 50 images obtained from our International Skin Imaging Collaboration dataset (n = 25) and pathologically confirmed lesions (n = 25). We compared the ability of our artificial intelligence to visually diagnose these 50 skin cancer lesions with a panel of three dermatologists. The artificial intelligence model better differentiated between melanoma vs. nonmelanoma with an area under the curve of 0.948. The three-panel member dermatologists correctly diagnosed a similar number of images (n = 35) as the artificial intelligence program (n = 34). Fleiss' kappa (ĸ) score for the raters and artificial intelligence indicated fair (0.247) agreement. However, the combined result of the dermatologists panel with the artificial intelligence assessments correctly identified 100% of the images from the test data set. Our artificial intelligence platform was able to utilize visual images to discriminate melanoma from nonmelanoma, using de-identified images. The combined results of the artificial intelligence with those of the dermatologists support the use of artificial intelligence as an efficient lesion assessment strategy to reduce time and expense in diagnoses to reduce delays in treatment.

Factors Contributing to Lingering Pain after Surgery: The Role of Patient Expectations.

BACKGROUND: Pain that lingers beyond the early weeks after the acute postoperative period is an important risk factor for chronic postsurgical pain. This study examined the hypothesis that patients' expectations about their postsurgical pain would be independently associated with lingering postsurgical pain. METHODS: The study included 3,628 patients who underwent diverse surgeries between February 2015 and October 2016 in a single U.S. tertiary hospital and participated in the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) observational study. Preoperatively, patients were asked about their expectations about pain 1 month after surgery. Patients were considered to have lingering postsurgical pain if they endorsed having pain in the area related to their surgeries during a follow-up survey obtained 1 to 3 months postoperatively. The independent associations between preselected perioperative variables and lingering postsurgical pain were evaluated. RESULTS: Of the cohort, 36% (1,308 of 3,628) experienced lingering postsurgical pain. Overall, two thirds (2,414 of 3,628) expected their postsurgical pain to be absent or improved from baseline, and 73% of these had their positive expectations fulfilled. A total of 19% (686 of 3,628) expected new, unabated, or worsened pain, and only 39% (257 of 661) of these had their negative expectations fulfilled. Negative expectations were most common in patients with presurgical pain unrelated to the reason for surgery, undergoing surgeries not typically performed to help alleviate pain. Endorsing negative expectations was independently associated with lingering postsurgical pain (odds ratio, 1.56; 95% CI, 1.23 to 1.98; P < 0.001). Additional major factors associated with lingering postsurgical pain included recollection of severe acute postoperative pain (odds ratio, 3.13; 95% CI, 2.58 to 3.78; P < 0.001), undergoing a procedure typically performed to help alleviate pain (odds ratio, 2.18; 95% CI, 1.73 to 2.75; P < 0.001), and preoperative pain related to surgery (odds ratio, 1.91; 95% CI, 1.52 to 2.40; P < 0.001). CONCLUSIONS: Lingering postsurgical pain is relatively common after diverse surgeries and is associated with both fixed surgical characteristics and potentially modifiable factors like pain expectations and severe acute postoperative pain.

Acculturation and Cancer Risk Behaviors among Pacific Islanders in Hawaii.

Background: To communicate research to the public, the National Cancer Institute developed the Health Information National Trends Survey (HINTS). However, as with most national health surveillance, including the Behavioral Risk Factor Surveillance System, HINTS data are not sufficient to address unique demographic subpopulations such as US Pacific Islanders (PIs). National sampling methods do not adequately reach participants from small, medically underserved populations. Aim: This study aims to document the cancer-relevant knowledge, attitudes, behaviors, and information-seeking practices of PIs in Hawaii (HI). Methods: We conducted a cross-sectional survey during 2017-2018 of Native Hawaiians, Chuukese, and Marshallese in HI using Respondent Driven Sampling (RDS) to recruit these geographically diffuse groups. The modified HINTS survey included questions about cancer knowledge, attitudes and behaviors, health communications, and cultural practices. Results: A total of 515 Native Hawaiians, 305 Chuukese, and 180 Marshallese completed the survey. Differences were found across a variety of cancer-related attitudes, knowledge, and behaviors. These groups also differed regarding acculturation, health locus of control, and trust in medical professionals. Native Hawaiians were significantly more acculturated (P=.0001) than Chuukese or Marshallese and more likely to smoke cigarettes (P=.0001). Among participants aged >50 years, we found no significant differences across ethnic groups (P=.30) for those completing a colon cancer screening (37%). However, only 27% were referred to screening by a physician. Conclusions: Cancer prevention programs are greatly needed for PIs in HI. This study provides knowledge concerning the efficiency of RDS to recruit participants, and the role of culture in communications influencing cancer risk behaviors, which may be generalizable to migrant PIs in the United States.

Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of SRC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and THJ-16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cells and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity, and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a potential therapeutic target for treatment of ATC patients and that SI-2 is a potent and promising candidate for a new therapeutic agent.

A Population-Based Analysis of Intraoperative Cardiac Arrest in the United States.

BACKGROUND: A new billable code for intraoperative cardiac arrest was introduced with the International Classification of Diseases, Tenth Revision, classification system. Using a national administrative database, we performed a retrospective analysis of intraoperative cardiac arrest in the United States. METHODS: Hospital admissions involving patients ≥18 years of age who underwent operating room procedures in 2016 were identified using the National Inpatient Sample. The primary outcome was the incidence of intraoperative cardiac arrest. Secondary outcomes included total cost of admission, in-hospital mortality, length of stay, and identification of risk factors associated with intraoperative cardiac arrest. Clinical risk factors were evaluated with multivariable logistic regression models using sampling weights and adjustment for clustering by strata. RESULTS: Of 35,675,421 admissions in 2016 in the United States, 9,244,861 admissions were identified in patients ≥18 years of age who underwent at least one operating room procedure. An estimated 5230 hospital admissions involved intraoperative cardiac arrest, yielding an estimated incidence of 5.7 (95% confidence interval [CI], 5.3-6.0) per 10,000 hospital admissions. Admissions involving an intraoperative cardiac arrest had a 35.7% in-hospital mortality, compared with 1.3% for admissions without intraoperative cardiac arrest. Intraoperative cardiac arrest was associated with a 15.44-fold (95% CI, 12.74-18.70; P < .001) increase in the risk-adjusted odds of in-hospital mortality and an additional $13,184 (95% CI, 9600-16,769; P < .001) of total admission costs. Selected factors independently associated with increased risk-adjusted odds of intraoperative cardiac arrest included: black or missing race; cardiac, thoracic, or vascular surgery; congestive heart failure; pulmonary circulation disorders; peripheral vascular disease; end-stage renal disease; and fluid and electrolyte disorders. CONCLUSIONS: In this population-based study of intraoperative cardiac arrest in the United States, admissions involving an intraoperative cardiac arrest were rare but were associated with high in-hospital mortality.

Impact of the Addition of Examples to the American Society of Anesthesiologists Physical Status Classification System.

Examples of comorbidities for the widely used American Society of Anesthesiologists physical status (ASA-PS) classification system were developed and approved in 2014. We conducted a retrospective cohort study of patients with 4 comorbidities included in the examples as warranting a specific minimum ASA-PS class. For each comorbidity subgroup, we used interrupted time-series models to compare ASA-PS underclassification for the periods before (2011-2014) and after (2015-2017) the introduction of examples. Rates of underclassification ranged from 4.8% to 38.7%. We observed no evidence of a significant impact on ASA-PS classification with the introduction of examples in 2014.

Association between postoperative complications and lingering post-surgical pain: an observational cohort study.

BACKGROUND: Post-surgical pain that lingers beyond the initial few-week period of tissue healing is a major predictor of pain chronification, which leads to substantial disability and new persistent opioid analgesic use. We investigated whether postoperative medical complications increase the risk of lingering post-surgical pain. METHODS: The study population consisted of patients undergoing diverse elective surgical procedures in an academic referral centre in the USA, between September 2013 and May 2017. Multivariable logistic regression, adjusting for confounding variables and patient-specific risk factors, was used to test for an independent association between any major postoperative complication and functionally limiting lingering pain 1-3 months after surgery, as obtained from patient self-reports. RESULTS: The cohort included 11 986 adult surgical patients; 10 562 with complete data. At least one complication (cardiovascular, respiratory, renal/gastrointestinal, wound, thrombotic, or neural) was reported by 13.3% (95% confidence interval: 12.7-14.0) of patients, and 19.7% (19.0-20.5%) reported functionally limiting lingering post-surgical pain. After adjusting for known risk factors, the patients were twice as likely (odds ratio: 2.04; 1.78-2.35) to report lingering post-surgical pain if they also self-reported a postoperative complication. Experiencing a complication was also independently predictive of lingering post-surgical pain (odds ratio: 1.95; 1.26-3.04) when complication data were extracted from the National Surgical Quality Improvement Program registry, instead of being obtained from patient self-report. CONCLUSIONS: Medical complications were associated with a two-fold increase in functionally limiting pain 1-3 months after surgery. Understanding the mechanisms that link complications to pathological persistence of pain could help develop future approaches to prevent persistent post-surgical pain.

Preoperative Diastolic Dysfunction and Postoperative Outcomes after Noncardiac Surgery.

OBJECTIVE: To determine if diastolic dysfunction is independently associated with increased mortality, acute kidney injury, and hospital length of stay after noncardiac surgery. DESIGN: Retrospective observational cohort. SETTING: Academic referral center. PARTICIPANTS: All patients undergoing noncardiac and nonliver-transplant surgeries at University of California - Los Angeles between April 2013 and October 2017, who also had transthoracic echocardiograms performed within 6 months preceding their procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' demographic, comorbidity, echocardiographic, and perioperative data were queried from the electronic health record. Diastolic dysfunction was graded by automated application of 2016 American Society of Echocardiography guidelines to queried echocardiographic measurements. During the study period, 12,871 eligible records were identified, of which 7,312 represented unique procedures with complete information. Twenty-three percent of patients had echocardiographic evidence of diastolic dysfunction (7.0% grade 1, 8.1% grade 2, 0.6% grade 3, and 7.5% nonspecific). Patients with diastolic dysfunction tended to be older and have higher American Society of Anesthesiologists scores with more comorbidities. Overall, 166 patients (2.3%) experienced an in-hospital death. After adjustment for potentially confounding variables, diastolic dysfunction was not significantly associated with increased in-hospital mortality, acute kidney injury, or hospital length of stay. CONCLUSIONS: Diastolic dysfunction does not appear to be associated with increased in-hospital mortality, acute kidney injury, or hospital length of stay in a cohort of noncardiac surgical patients at an academic medical center. These results highlight uncertainties in perioperative risk determination.

Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors.

Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited options for treatment. Targeting epigenetic modifications via interfering with the interaction between the bromodomain and extra-terminal domain (BET) proteins and acetylated histones by using BET inhibitors (e.g., JQ1) has shown some efficacy in thyroid cancer. To improve the efficacy, an inhibitor of MEK, trametinib, was tested together with JQ1 as a combined treatment via cell-based approaches and xenograft studies. We examined the effects of combined treatment of JQ1 and trametinib on the proliferation of human ATC cell lines (THJ-11T and THJ-16) in vitro. We further evaluated the effects of the combined treatment on tumor development in vivo using mouse xenograft models. We elucidated the underlying molecular pathways affected by double treatment. We showed that the combined treatment totally blocked proliferation, while either JQ1 or trametinib alone only had partial effects. Combined treatment suppressed MYC expression more than single treatment, resulting in decreased expression of pro-survival regulators and increased pro-apoptotic regulators to collaboratively induce apoptosis. In xenograft studies, single treatment only partially inhibited tumor growth, but the combined treatment inhbited tumor growth by >90%. The reduction of tumor growth was mediated by synergistic suppression of MYC, to affect apoptotic regulators to markedly promote tumor apoptosis. Combined treatment of BET and MEK-ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC.

Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer.

Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer. In vivo studies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/- mice). The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor ß (denoted as PV) and a deletion of one single allele of the Pten gene. The ThrbPV/PVPten+/- mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obese ThrbPV/PVPten+/- mice (HFD-ThrbPV/PVPten+/- mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-ThrbPV/PVPten+/- mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-ThrbPV/PVPten+/- with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene.

Patients with mutations of the THRA gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRα1 (denoted as PV; Thra1PV/+ mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using Thra1PV/+ mice, we explored how the TRα1PV mutant acted to cause abnormalities in erythropoiesis. Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, ß-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3-directly regulated gene and that TRα1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. These results provide new insights into how TRα1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders.

Inhibition of STAT3 signaling blocks obesity-induced mammary hyperplasia in a mouse model.

Compelling epidemiologic evidence indicates that obesity is a risk factor for human cancers, including breast. However, molecular mechanisms by which obesity could contribute to the development of breast cancer remain unclear. To understand the impact of obesity on breast cancer development, we used a mutant mouse that expresses a mutated thyroid hormone receptor ß (denoted as PV) with haplodeficiency of the Pten gene (ThrbPV/PVPten+/- mice). We previously showed that adult nulliparous female ThrbPV/PVPten+/- mice developed extensive mammary hyperplasia and breast tumors. In this study, we induced obesity in ThrbPV/PVPten+/- mice by feeding them a high fat diet (HFD). We found HFD exacerbated the extent of mammary hyperplasia in ThrbPV/PVPten+/- mice. HFD elevated serum leptin levels but had no effect on the levels of serum thyroid stimulating hormone, thyroid hormones, and estrogens. Molecular analysis showed that the obesity-induced hyperplasia was mediated by the leptin/leptin receptor-JAK1-STAT3 pathway to increase key cell cycle regulators to stimulate mammary epithelial cell proliferation. Activated STAT3 signaling led to altered expression in the key regulators of epithelial-mesenchymal-transition (EMT) to augment invasiveness and migration of mammary proliferating epithelial cells. Moreover, treatment of HFD-ThrbPV/PVPten+/- mice with a STAT3 inhibitor, S3I-201, markedly reversed the obesity-induced mammary hyperplasia and reduced EMT signals to lessen cell invasiveness and migration. Our studies not only elucidated how obesity could contribute to mammary hyperplasia at the molecular level, but also, importantly, demonstrated that inhibition of the STAT3 activity could be a novel treatment strategy for obesity-induced breast cancer progression.

Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer.

Context: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated. Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models. Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells. Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling. Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model.

PURPOSE: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. EXPERIMENTAL DESIGN: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. RESULTS: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. CONCLUSIONS: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.

Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor ß.

We have recently identified that phosphorylation at tyrosine (Y)406 is critical for the tumor suppressor functions of the thyroid hormone receptor ß1 (TRß) in a breast cancer line. However, still unclear is whether the critical tumor suppressor role of phosphorylated Y406 of TRß is limited to only breast cancer cells or could be extended to other cell types. In the present studies, we addressed this question by stably expressing TRß, a mutated TRß oncogene (PV), or a TRß mutated at Y406 (TRßY406F) in rat PCCL3 thyroid follicular cells and evaluated their tumor characteristics in athymic mice with elevated thyroid stimulating hormone. PCCL3 cells stably expressing PV (PCCL3-PV), TRßY406F (PCCL3-TRßY406F), or vector only (PCCL3-Neo) developed tumors with sizes in the rank order of TRßY406F>PV = Neo, whereas PCCL3 cells expressing TRß (PCCL3-TRß) barely developed tumors. As evidenced by markedly elevated Ki67, cyclin D1, and p-Rb protein abundance, proliferative activity was high in PV and TRßY406F tumors, but low in TRß tumors. These results indicate that TRß acted as a tumor suppressor in PCCL3 cells, whereas TRßY406F and PV had lost tumor suppressor activity. Interestingly, TRßY406F tumors had very low necrotic areas with decreased TNFα-NFκB signaling to lower apoptotic activity. In contrast, PV tumors had prominent large necrotic areas, with no apparent changes in TNFα-NFκB signaling, indicating distinct oncogenic activities of mutant PV and TRßY406F. Thus, the present studies uncovered a novel mechanism by which TRß could function as a tumor suppressor through modulation of the TNFα-NFκB signaling. © 2016 Wiley Periodicals, Inc.

SAHA-induced loss of tumor suppressor Pten gene promotes thyroid carcinogenesis in a mouse model.

Thyroid cancer is on the rise. Novel approaches are needed to improve the outcome of patients with recurrent and advanced metastatic thyroid cancers. FDA approval of suberoylanilide hydroxamic acid (SAHA; vorinostat), an inhibitor of histone deacetylase, for the treatment of hematological malignancies led to the clinical trials of vorinostat for advanced thyroid cancer. However, patients were resistant to vorinostat treatment. To understand the molecular basis of resistance, we tested the efficacy of SAHA in two mouse models of metastatic follicular thyroid cancer: Thrb(PV/PV) and Thrb(PV/PV)Pten(+/-) mice. In both, thyroid cancer is driven by overactivation of PI3K-AKT signaling. However, the latter exhibit more aggressive cancer progression due to haplodeficiency of the tumor suppressor, the Pten gene. SAHA had no effects on thyroid cancer progression in Thrb(PV/PV) mice, indicative of resistance to SAHA. Unexpectedly, thyroid cancer progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice with accelerated occurrence of vascular invasion, anaplastic foci, and lung metastasis. Molecular analyses showed further activated PI3K-AKT in thyroid tumors of SAHA-treated Thrb(PV/PV)Pten(+/-) mice, resulting in the activated effectors, p-Rb, CDK6, p21(Cip1), p-cSrc, ezrin, and matrix metalloproteinases, to increase proliferation and invasion of tumor cells. Single-molecule DNA analysis indicated that the wild-type allele of the Pten gene was progressively lost, whereas carcinogenesis progressed in SAHA-treated Thrb(PV/PV)Pten(+/-) mice. Thus, this study has uncovered a novel mechanism by which SAHA-induced loss of the tumor suppressor Pten gene to promote thyroid cancer progression. Effectors downstream of the Pten loss-induced signaling may be potential targets to overcome resistance of thyroid cancer to SAHA.

Metformin blocks progression of obesity-activated thyroid cancer in a mouse model.

Compelling epidemiologic evidence indicates that obesity is associated with a high risk of human malignancies, including thyroid cancer. We previously demonstrated that a high fat diet (HFD) effectively induces the obese phenotype in a mouse model of aggressive follicular thyroid cancer (ThrbPV/PVPten+/-mice). We showed that HFD promotes cancer progression through aberrant activation of the leptin-JAK2-STAT3 signaling pathway. HFD-promoted thyroid cancer progression allowed us to test other molecular targets for therapeutic opportunity for obesity-induced thyroid cancer. Metformin is a widely used drug to treat patients with type II diabetes. It has been shown to reduce incidences of neoplastic diseases and cancer mortality in type II diabetes patients. The present study aimed to test whether metformin could be a therapeutic for obesity-activated thyroid cancer. ThrbPV/PVPten+/-mice were fed HFD together with metformin or vehicle-only, as controls, for 20 weeks. While HFD-ThrbPV/PVPten+/-mice had shorter survival than LFD-treated mice, metformin had no effects on the survival of HFD-ThrbPV/PVPten+/-mice. Remarkably, metformin markedly decreased occurrence of capsular invasion and completely blocked vascular invasion and anaplasia in HFD-ThrbPV/PVPten+/-mice without affecting thyroid tumor growth. The impeded cancer progression was due to the inhibitory effect of metformin on STAT3-ERK-vimentin and fibronectin-integrin signaling to decrease tumor cell invasion and de-differentiation. The present studies provide additional molecular evidence to support the link between obesity and thyroid cancer risk. Importantly, our findings suggest that metformin could be used as an adjuvant in combination with antiproliferative modalities to improve the outcome of patients with obesity-activated thyroid cancer.