Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway.

As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

A novel LncRNA PTH-AS upregulates interferon-related DNA damage resistance signature genes and promotes metastasis in human breast cancer xenografts.

Long noncoding RNAs (lncRNAs) are important tissue-specific regulators of gene expression, and their dysregulation can induce aberrant gene expression leading to various pathological conditions, including cancer. Although many lncRNAs have been discovered by computational analysis, most of these are as yet unannotated. Herein, we describe the nature and function of a novel lncRNA detected downstream of the human parathyroid hormone (PTH) gene in both extremely rare ectopic PTH-producing retroperitoneal malignant fibrous histiocytoma and parathyroid tumors with PTH overproduction. This novel lncRNA, which we have named "PTH-AS," has never been registered in a public database, and here, we investigated for the first time its exact locus, length, transcription direction, polyadenylation, and nuclear localization. Microarray and Gene Ontology analyses demonstrated that forced expression of PTH-AS in PTH-nonexpressing human breast cancer T47D cells did not induce the ectopic expression of the nearby PTH gene but did significantly upregulate Janus kinase-signal transducer and activator of transcription pathway-related genes such as cancer-promoting interferon-related DNA damage resistance signature (IRDS) genes. Importantly, we show that PTH-AS expression not only enhanced T47D cell invasion and resistance to the DNA-damaging drug doxorubicin but also promoted lung metastasis rather than tumor growth in a mouse xenograft model. In addition, PTH-AS-expressing T47D tumors showed increased macrophage infiltration that promoted angiogenesis, similar to IRDS-associated cancer characteristics. Although the detailed molecular mechanism remains imperfectly understood, we conclude that PTH-AS may contribute to tumor development, possibly through IRDS gene upregulation.

Relationship between somatic symptoms with menstruation and intention to leave work among university hospital nurses in Japan: a cross-sectional study.

PURPOSE: This study investigated the association between menstrual symptoms and the intention to leave work among female nurses in Japan. METHODS: This cross-sectional study investigated female nurses (n = 317) at two university hospitals. The items measured were their characteristics (e.g., age, body mass index), "intention to leave" work, somatic symptoms related with menstruation, self-reported menstrual characteristics (e.g., pain), physical workloads (e.g., working hours and night shifts) and psychological workloads, measured with the Copenhagen Burnout Inventory (CBI), and the Job Content Questionnaire (JCQ). Participants with at least four somatic symptoms (e.g., cold, fatigue) which are present during their menstrual cycles were considered to have "somatic symptoms associated with menstruation." We also measured serum ovarian and gonadotropin-releasing hormones. RESULTS: Approximately 40% of women answered "intention to leave" work, and 17% had "somatic symptoms associated with menstruation." Multiple logistic regression analysis suggested that nurses reporting "somatic symptoms associated with menstruation" were more likely to have "intention to leave" work: the adjusted odds ratios (AOR, 95% confidence interval [CI]) were 2.15 (1.12-4.11) in the personal-burnout model, 2.23 (1.16-4.31) in the work-related burnout model, 2.91 (1.52-5.56) in the client-related burnout model; 2.96 (1.50-5.82) in the JCQ model. There was no association between serum and gonadotropin hormones and the intention to leave. CONCLUSION: Somatic symptoms with menstruation were associated with intention to leave work among female Japanese nurses. Intervention for somatic symptoms with menstruation might support nurses to continue work.

[Curative Resection after Chemotherapy for Advanced Extensive Cholangiocarcinoma-A Case Report].

A 73-year-old, male patient presented with the chief complaint of epigastric pain and received the diagnosis of extensive cholangiocarcinoma after a close examination. Extensive extension of the malignancy into the right and left hepatic ducts precluded a curative resection, and the patient received GC therapy. After 11 courses of GC over about 1 year, no new lesions or tumor progression was observed, and a bile duct mapping biopsy was performed to investigate the possibility of resection conversion. The results showed a marked decrease in atypia, and reactive atypia was diagnosed. A pancreaticoduodenectomy was performed, and histopathologically negative margins were obtained. The response to treatment was Grade Ⅱa according to the Evans classification. At 23 months after the start of treatment and 12 months after surgery, the patient is recurrence-free without adjuvant chemotherapy. Although the evidence for conversion surgery for biliary tract cancer has not been established, the long-term outcomes may be favorable.

[A Case of a Two-Stage Robotic-Assisted Surgery for a Neuroendocrine Tumor of the Pancreatic Tail with Simultaneous Single Liver Metastasis].

As medical insurance coverage for robotic surgery has been expanded in the field of gastrointestinal surgery in Japan, the number of cases undergoing robotic surgery for hepato-biliary-pancreatic disease has been increasing. Therefore, cases with malignant tumors and metastatic lesions tend to undergo robotic operation for both primary tumors and metastases. Herein, we report a case of neuroendocrine tumor(NET)in the pancreatic tail with simultaneous single liver metastasis, which was treated with two-stage robotic-assisted surgery. A 67-year-old female underwent a computed tomography scan and a hypovascularized tumor in the pancreatic tail region and liver was found. A biopsy of the pancreatic tumor by endoscopic ultrasound-guided fine needle aspiration demonstrated a NET G1-2. The liver lesion was diagnosed as a metastatic tumor, considering the other examinations. The patient underwent a robotic distal pancreatectomy(RDP)and was histopathologically diagnosed as NET G2. Sixty-three days after the RDP, a two-stage partial liver resection for the metastatic tumor was performed under robotic assistance. Curative resection was achieved through two-stage robot-assisted surgery, there were no postoperative complications.

[Treatment Strategies for Liver Oligometastases of Esophageal Cancer].

Benefits of local therapy for liver oligometastases of esophageal cancer has not been established. There are 2 cases of resection for liver oligometastases of esophageal cancer. Case 1: A 65-year-old male diagnosed with liver metastasis of esophageal cancer 12 months after initial treatment. A tumor located in segment 7 was resected after 6 months of chemotherapy. Case 2: A 71-year-old female diagnosed with liver metastasis of esophageal cancer 14 months after initial treatment. During 6 months of chemotherapy, tumor diameter increased but there were no new lesions. The tumor located in segment 8 was resected. In both cases, R0 resection was performed without intraoperative injury to the reconstructed esophagus. They had a recurrence free survival of more than 5 months. Resection of liver metastasis of esophageal cancer may be useful in combination with drug therapy in case it was diagnosed with liver oligometastases.

Workplace resources, mentorship, and burnout in early career physician-scientists: a cross sectional study in Japan.

BACKGROUND: Physician-scientists are a vital segment of the healthcare workforce, but they may face significant challenges balancing and integrating clinical responsibilities, scientific research, and domestic responsibilities. This study investigates factors associated with burnout among highly successful early career physician-researchers in Japan. METHOD: Among 1790 physician awardees of Grant-in-Aid for Young Scientists by the Japanese Ministry in 2014-2015, 490 participated in this cross-sectional survey in 2016 (usable response rate 23.8%). The primary outcome was psychological burnout, measured by the Copenhagen Burnout Inventory (i.e., personal burnout, work-related burnout, and patient-related burnout). "Workplace resources" in our study refers to the presence of career education in the workplace, promotion of gender equity, well-being consultation services on "career and work," "research," "harassment," and/or "mental health," as well as the presence of a role model in the workplace who has perceived good work-life balance. RESULTS: Among 408 physician-researchers (75% male, mean age 37 yrs), personal burnout scores were slightly higher in women than in men (mean score, 41.9 points vs. 36.7 points, difference, 5.2, 95% confidence interval, 0.5-9.9, p = 0.029), but work-related and patient-related burnout scores did not differ significantly between genders. Over half of women (64%) and men (58%) had a mentor (p = 0.374). In multivariable general linear regression models, personal burnout scores were higher for women (ß = 4.98, p = 0.045), and lower among those who had a mentor (ß = - 5.82, p = 0.010) and whose workplaces had well-being consultation services (ß = - 0.79, p = 0.022). Work-related burnout scores were lower among those with larger amounts of grant funding (ß = - 4.70, p = 0.013), a mentor (ß = - 6.12, p = 0.002), well-being consultation services (ß = - 0.78, p = 0.008) and a role model with a perceived good work-life balance (ß = - 4.00, p = 0.038). Patient-related burnout scores were higher among physician-scientists aged older than 37 years (ß = 6.25, p = 0.002) and those who had board certification (ß = 9.01, p = 0.017), while these scores were lower among those had larger amounts of funding (ß = - 5.01, p = 0.006) or a mentor (ß = - 5.35, p = 0.006). CONCLUSIONS: Workplace resources and mentorship appear to be associated with lower levels of psychological burnout for both men and women early career physician-scientists.

Direct and Indirect Harassment Experiences and Burnout among Academic Faculty in Japan.

The purpose of this study is three-fold: (1) to compare harassment (sexual, gender, and academic harassment both directly and indirectly experienced - i.e. "directly harassed" and "have seen or heard of someone who experienced harassment", respectively) experienced by males and females, (2) to investigate whether such experiences correlate with burnout, and (3) to explore whether social support might mitigate any such relationship between harassment and burnout. This cross-sectional study was conducted at a private university in Japan in February 2014 and is based on a work-life balance survey obtained from 330 academic faculty members. We investigated the association between each of the six subcategories of harassment (direct and indirect forms of each of the three types) and burnout using general linear regression models; we then evaluated interactions between harassment and social support in these models. The prevalence of direct and indirect experiences of harassment was higher in females than in males for all three types of harassment. Males showed higher burnout scores if they had direct experiences of harassment. There were significant interactions between social support and the direct experience of harassment; high social support mitigated the effect size of direct harassment on burnout among males. Females showed higher burnout scores if they had indirect experiences of harassment. However, the same buffering effect of social support on burnout as observed in males was not observed in females. Direct harassment experiences increased the risk of burnout in males, and indirect harassment experiences increased burnout in females.

Intrinsic ubiquitin E3 ligase activity of histone acetyltransferase Hbo1 for estrogen receptor α.

Estrogen receptors (ER) are important transcription factors to relay signals from estrogen and to regulate proliferation of some of breast cancers. The cycling of estrogen-induced DNA binding and ubiquitin-linked proteolysis of ER potentiates ER-mediated transcription. Indeed, several transcriptional coactivators for ER-dependent transcription ubiquitinate ER. Histone acetyltransferase (HAT) Hbo1/KAT7/MYST2, involved in global histone acetylation, DNA replication, transcription, and cellular proliferation, promotes proteasome-dependent degradation of ERα through ubiquitination. However, molecular mechanism for ubiquitination of ERα by Hbo1 is unknown. Here we report the intrinsic ubiquitin E3 ligase activity of Hbo1 toward the ERα. The ligand, estradiol-17ß, inhibited E3 ligase activity of Hbo1 for ERα in vitro, whereas hyperactive ERα mutants from metastatic breast cancers resistant to hormonal therapy, were better substrates for ERα ubiquitination by Hbo1. Hbo1 knock-down caused increase in ERα expression. Hbo1 is another ERα coactivator that ubiquitinates ERα.

Effects of gaps in priorities between ideal and real lives on psychological burnout among academic faculty members at a medical university in Japan: a cross-sectional study.

BACKGROUND: Accumulating evidence from medical workforce research indicates that poor work/life balance and increased work/home conflict induce psychological distress. In this study we aim to examine the existence of a priority gap between ideal and real lives, and its association with psychological burnout among academic professionals. METHODS: This cross-sectional survey, conducted in 2014, included faculty members (228 men, 102 women) at a single medical university in Tokyo, Japan. The outcome of interest was psychological burnout, measured with a validated inventory. Discordance between ideal- and real-life priorities, based on participants' responses (work, family, individual life, combinations thereof), was defined as a priority gap. RESULTS: The majority (64%) of participants chose "work" as the greatest priority in real life, but only 28% chose "work" as the greatest priority in their conception of an ideal life. Priority gaps were identified in 59.5% of respondents. A stepwise multivariable general linear model demonstrated that burnout scores were associated positively with respondents' current position (P < 0.0018) and the presence of a priority gap (P < 0.0001), and negatively with the presence of social support (P < 0.0001). Among participants reporting priority gaps, burnout scores were significantly lower in those with children than in those with no children (P interaction = 0.011); no such trend was observed in participants with no priority gap. CONCLUSIONS: A gap in priorities between an ideal and real life was associated with an increased risk of burnout, and the presence of children, which is a type of "family" social support, had a mitigating effect on burnout among those reporting priority gaps.

Wild-type and specific mutant androgen receptor mediates transcription via 17ß-estradiol in sex hormone-sensitive cancer cells.

We previously encountered regulatory processes wherein dihydrotestosterone (DHT) exerted its inhibitory effect on parathyroid hormone-related protein (PTHrP) gene repression through the estrogen receptor (ER)α, but not the androgen receptor (AR), in breast cancer MCF-7 cells. Here, we investigated whether such aberrant ligand-nuclear receptor (NR) interaction is present in prostate cancer LNCaP cells. First, we confirmed that LNCaP cells expressed large amounts of AR at negligible levels of ERα/ß or progesterone receptor. Both suppression of PTHrP and activation of prostate-specific antigen genes were observed after independent administration of 17ß-estradiol (E2), DHT, or R5020. Consistent with the notion that the LNCaP AR lost its ligand specificity due to a mutation (Thr-Ala877), experiments with siRNA targeting the respective NR revealed that the AR monopolized the role of the mediator of shared hormone-dependent regulation, which was invariably associated with nuclear translocation of this mutant AR. Microarray analysis of gene regulation by DHT, E2, or R5020 disclosed that more than half of the genes downstream of the AR (Thr-Ala877) overlapped in the LNCaP cells. Of particular interest, we realized that the AR (wild-type [wt]) and AR (Thr-Ala877) were equally responsible for the E2-AR interactions. Fluorescence microscopy experiments demonstrated that both EGFP-AR (wt) and EGFP-AR (Thr-Ala877) were exclusively localized within the nucleus after E2 or DHT treatment. Furthermore, reporter assays revealed that some other cancer cells exhibited aberrant E2-AR (wt) signaling similar to that in the LNCaP cells. We herein postulate the presence of entangled interactions between wt AR and E2 in certain hormone-sensitive cancer cells.

Molecular status of pituitary carcinoma and atypical adenoma that contributes the effectiveness of temozolomide.

There have been several reports of temozolomide (TMZ) treatment of pituitary carcinomas and atypical adenomas. O(6)-methyl-guanine-DNA methyltransferase is not the sole molecule determining the sensitivity to TMZ in pituitary carcinomas and atypical adenomas. The Japan Society of Hypothalamic and Pituitary Tumors study suggests that MSH6, one of mismatch repair pathway enzyme, fulfills a contributory role to the efficacy of TMZ treatment for pituitary carcinomas and atypical adenomas. The preserved MSH6 function might be essential for the responsiveness to TMZ treatment in pituitary carcinomas and atypical adenomas.

Accumulation of senescent cells in the adrenal gland induces hypersecretion of corticosterone via IL1ß secretion.

Aging progresses through the interaction of metabolic processes, including changes in the immune and endocrine systems. Glucocorticoids (GCs), which are regulated by the hypothalamic-pituitary-adrenal (HPA) axis, play an important role in regulating metabolism and immune responses. However, the age-related changes in the secretion mechanisms of GCs remain elusive. Here, we found that corticosterone (CORT) secretion follows a circadian rhythm in young mice, whereas it oversecreted throughout the day in aged mice >18 months old, resulting in the disappearance of diurnal variation. Furthermore, senescent cells progressively accumulated in the zF of the adrenal gland as mice aged beyond 18 months. This accumulation was accompanied by an increase in the number of Ad4BP/SF1 (SF1), a key transcription factor, strongly expressing cells (SF1-high positive: HP). Removal of senescent cells with senolytics, dasatinib, and quercetin resulted in the reduction of the number of SF1-HP cells and recovery of CORT diurnal oscillation in 24-month-old mice. Similarly, administration of a neutralizing antibody against IL1ß, which was found to be strongly expressed in the adrenocortical cells of the zF, resulted in a marked decrease in SF1-HP cells and restoration of the CORT circadian rhythm. Our findings suggest that the disappearance of CORT diurnal oscillation is a characteristic of aging individuals and is caused by the secretion of IL1ß, one of the SASPs, from senescent cells that accumulate in the zF of the adrenal cortex. These findings provide a novel insight into aging. Age-related hypersecretory GCs could be a potential therapeutic target for aging-related diseases.

Delayed bowel stenosis following subtotal resection of the small intestine for non-occlusive mesenteric ischemia.

We report herein a case of delayed bowel stenosis after surgery for non-occlusive mesenteric ischemia (NOMI), which was successfully treated with endoscopic stenting. The patient was a 78-year-old woman who underwent an emergency laparotomy for NOMI and duodeno-ileal anastomosis. Necrosis was observed in almost all areas of the small intestine except for the beginning of the jejunum and the end of the ileum. Postoperatively, the patient was discharged with central venous nutrition, but was readmitted on postoperative day 54 with a diagnosis of postoperative ileus. The patient failed to respond to conservative treatment. Fluoroscopic endoscopy revealed wall stiffness and circumferential stenosis in the ascending colon at a different site from that of the anastomosis. Based on this finding, delayed stenosis of the ascending colon after NOMI treatment was diagnosed. Bougie dilatation was performed for the stenosis, leading to temporary improvement. However, stenosis along with ileus soon recurred. To prevent restenosis, a metallic stent was endoscopically implanted at the stenotic site. Thereafter, the patient was discharged without any further episodes of restenosis. Delayed bowel stenosis may occur after a subtotal resection of the small intestine for NOMI. Endoscopic stenting is an effective treatment option if resection is difficult.

Histone acetyltransferase Hbo1 destabilizes estrogen receptor α by ubiquitination and modulates proliferation of breast cancers.

The estrogen receptor (ER) is a key molecule for growth of breast cancers. It has been a successful target for treatment of breast cancers. Elucidation of the ER expression mechanism is of importance for designing therapeutics for ER-positive breast cancers. However, the detailed mechanism of ER stability is still unclear. Here, we report that histone acetyltransferase Hbo1 promotes destabilization of estrogen receptor α (ERα) in breast cancers through lysine 48-linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its activity for ERα ubiquitination. Depletion of Hbo1 and anti-estrogen treatment displayed a potent growth suppression of breast cancer cell line. Hbo1 modulated transcription by ERα. Mutually exclusive expression of Hbo1 and ERα was observed in roughly half of the human breast tumors examined in the present study. Modulation of ER stability by Hbo1 in breast cancers may provide a novel therapeutic possibility.

Modified S/MAR episomal vectors for stably expressing fluorescent protein-tagged transgenes with small cell-to-cell fluctuations.

We modified and tested scaffold/matrix attachment region (S/MAR) episomal vectors. The new vectors would be useful in obtaining cells stably expressing fluorescent protein-tagged transgenes with small, mostly within 10-fold cell-to-cell fluctuations. In the vectors, the same transcript directs episomal replication and expression of transgene/antibiotic marker, and only antibiotic selection without any other extra steps was sufficient to obtain desired stable cells, including those expressing two different proteins simultaneously. Furthermore, the two test cases (expression of human growth hormone in AtT20 and four protein kinase C isoforms in HEK293) would prove to be useful in visualizing and analyzing regulatory processes involving these proteins.

Urinary growth hormone level and insulin-like growth factor-1 standard deviation score (IGF-SDS) can discriminate adult patients with severe growth hormone deficiency.

Adult growth hormone (GH) deficiency (AGHD) in Japan is diagnosed based on peak GH concentrations during GH provocative tests such as GHRP-2 stimulation test. In this study, we aimed to evaluate the ability of serum insulin-like growth factor-1 (sIGF-1) and urinary GH (uGH) at the time of awakening to diagnose AGHD. Fifty-nine patients with pituitary disease (32 men and 27 women; age 20-85 y (57.5 ± 15.5, mean ± SD) underwent GHRP-2 stimulation and sIGF-1 testing. Thirty-six and 23 patients were diagnosed with and without severe AGHD, respectively based on a peak GH response of <9 ng/mL to GHRP-2 stimulation. Serum IGF-1 was evaluated as a standard deviation score (IGF-1 SDS) based on age and sex. We determined whether uGH levels in urine samples from 42 of the 59 patients at awakening were above or below the sensitivity limit. We evaluated IGF-1 SDS and uGH levels in a control group of 15 healthy volunteers. Values for IGF-1 SDS were significantly lower in patients with, than without (-2.07 ± 1.77 vs.-0.03 ± 0.92, mean ± SD; p < 0.001) AGHD whereas the range of IGF-1 SDS substantially overlapped at > -1.4. IGF-1 SDS discriminated AGHD more effectively in patients aged ≤60 years. The χ2 test revealed a statistical relationship between uGH and AGHD (test statistic: 7.0104 ≥ χ2 (1; 0.01) = 6.6349). When IGF-1 SDS is < -1.4 or uGH is below the sensitivity limit, AGHD can be detected with high sensitivity.

Body-first approach of laparoscopic cholecystectomy for minimizing vasculobiliary injury: Initial experience.

INTRODUCTION: Vasculobiliary injury (VBI) is a rare but critical complication of laparoscopic cholecystectomy (Lap-C). Dividing first the gallbladder body and then the gallbladder neck from the gallbladder bed (the "body-first approach") may decrease the possibility of VBI. METHODS: The surgical outcome of 62 patients who underwent Lap-C with a body-first approach were evaluated. In this procedure, after serosal resection of the gallbladder, the gallbladder body is divided from the cystic plate; then the gallbladder neck and cystic duct are isolated. No connective tissue of the hepatic hilum is touched. RESULTS: A total of five patients had anatomical anomalies of the biliary tract that raised concerns of cholecystectomy. Furthermore, seven patients underwent subtotal cholecystectomy. No patients required conversion to open surgery, and none developed VBI or postoperative complications of Clavien-Dindo grade 3a or worse. CONCLUSION: The body-first approach may minimize the risk of VBI during Lap-C.

Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice.

Saposin D-deficient (Sap-D(-/-)) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino d-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D(-/-) mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10∼12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-mo-long water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D(-/-) mice.

Negative regulation of parathyroid hormone-related protein expression by steroid hormones.

Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor α, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.