The pituitary tumor-transforming gene 1 (PTTG1) is an oncogene involved in chromosomal segregation, DNA repair, apoptosis, and metabolism. PTTG1 can be used for clinical diagnosis and treatment and is a potential target for oropharyngeal carcinoma. The proliferation and viability of Cal27 and FaDu cells were assessed using the CCK-8 assay. Real-time PCR and western blotting, respectively, were used to analyze the mRNA and protein expression levels of PTTG1 and IFIH1. The interaction between PTTG1 mRNA and the translational regulatory protein IFIH1 was analyzed using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. PTTG1 protein was significantly overexpressed in oropharyngeal carcinoma, whereas PTTG1 mRNA was not. We hypothesized that a translation regulatory protein plays a post-transcriptional role in PTTG1. The IFIH1 protein specifically bound to the 42-52 nt region of PTTG1 mRNA, promoted the translation of PTTG1, and promoted the proliferation of oropharyngeal cancer cells. Administration of the PTTG1 inhibitor PHA-848125 and silencing of IFIH1 synergistically decreased the expression of PTTG1, inhibited the proliferation of oropharyngeal cancer cells, and indicated a good prognosis. We found that the IFIH1-PTTG1 axis could regulate the PHA-848125 response and functionally mediate inter-individual oropharyngeal cancer susceptibility and prognosis. This study aimed to confirm the upstream regulatory genes of PTTG1 and further investigate the specific interactions in this signaling pathway, which will provide a new approach for the treatment of oropharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) and oropharyngeal carcinoma (OPC) are subtypes of head and neck cancer with different treatment effects due to the heterogeneity of tumor microenvironments. This study was to investigate the distinctive tumor microenvironments of NPC and OPC. Analyzing single-cell data from 10 cases of each subtype, we reveal significant differences in cellular composition, with NPC microenvironment dominated by T/NK and B cells, and OPC characterized by prevalent epithelial cells and fibroblasts. Dynamic transitions of CD8 T cells are observed in both tumor types, involving shifts from naivety to cytotoxicity, proliferation, and eventual exhaustion/exhausted states. Additionally, Tregs exhibit heightened proliferative abilities in later developmental stages, concomitant with exhaustion. These highly proliferative T cells and Tregs manifest elevated glycolysis and lactate metabolism activities. Furthermore, we explore intercellular communication between glycolytic malignant epithelial cells and these proliferative T cells. These findings offer comprehensive insights into the heterogeneity of tumor microenvironments and provide a solid foundation for future therapeutic strategies and targeted interventions.

OBJECTIVE: This study aimed to explore the characteristics of human papillomavirus (HPV) in oropharyngeal carcinoma (OPC), in order to provide a new theoretical basis for the prevention, treatment, and management of OPC.
METHODS: The electronic databases were searched available publications relevant to HPV infection and OPC. Studies were collected until July, 2023. The effect sizes were combined using R 4.2.2 software. Subgroup and sensitivity analyses were performed to explore the sources of heterogeneity. Funnel plot and Egger\'s test were used to assess the publication bias.
RESULTS: Seventy-one studies were included with 10,908 OPC patients. The pooled prevalence of HPV and HR-HPV infection was 44.22% and 43.94%, respectively. The genotypes of HR-HPV were HPV16 (37.24%), HPV33 (2.44%), HPV18 (1.64%), HPV35 (1.53%), and HPV58 (0.89%). The highest HPV infection was in North America (66.87%), Oceania (43.09%), and Europe (41.49%), lowest in Africa (4.89%). Females exhibited higher HPV infection (43.18% vs 34.59% in males). Top subsites of HPV infection was tonsil (45.78%), followed by base of tongue (36.66%). Infection was higher in OPC patients aged > 60 (38.15%) than < 60 (34.73%). The prevalence of HPV infection in stage I-II of OPC patients is higher than that in stage III-IV.
CONCLUSIONS: HPV genotyping (16, 18, 33, 35, 58) is a key factor in the prevention and treatment of OPC. Identifying tonsils, base of tongue, and soft palate as common subsites to improve early detection. Elderly women with high HPV infection require attention to risk management and health education for prevention.

The incidence of oropharyngeal squamous cell carcinomas (OPSCC) has increased in recent decades, and human papillomavirus (HPV) infection is the main cause of OPSCC. The data regarding causes of death (CODs) are vitally important in informing follow-up strategies and revising treatment strategies to deal with any possible preventable treatment-related COD. However, limited studies have assessed the competing COD by HPV status in patients with OPSCC.
We aimed to analyze the distribution of the competing COD according to HPV status in OPSCC.
We retrospectively included stage I-IVB patients with OPSCC from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. The association between HPV status and head and neck cancer-specific mortality (HNCSM), second primary cancer mortality (SPCM), and noncancer-caused mortality (NCCM) were analyzed. The chi-square test, Kaplan-Meier analysis, and Fine and Gray model were used for statistical analysis.
We included 5852 patients in this study and 73.2% (n=4283) of them had HPV-related tumors. A total of 1537 (26.3%) patients died, including 789 (51.3%), 333 (21.7%), and 415 (27%) patients who died from head and neck cancer, second cancer, and noncancer causes, respectively. The 5-year HNCSM, SPCM, NCCM, and overall mortality were 14.7%, 6.5%, 7.7%, and 26.4%, respectively. Those with HPV-positive disease had a lower cumulative incidence of HNCSM (subdistribution hazard ratio [sHR] 0.362, 95% CI 0.315-0.417; P<.001), SPCM (sHR 0.400, 95% CI 0.321-0.496; P<.001), and NCCM (sHR 0.460, 95% CI 0.378-0.560; P<.001) than those with HPV-negative disease. The 5-year risk of HNCSM was 26.9% and 10.7% in those with HPV-negative and HPV-positive disease, respectively (P<.001). The 5-year risk of SPCM was 12.4% and 4.6% in those with HPV-negative and HPV-positive disease, respectively (P<.001). The 5-year risk of NCCM of death was 13.7% and 5.8% in those with HPV-negative and HPV-positive disease, respectively (P<.001). Using the Fine and Gray competing-risks model, our results show that those with HPV-negative tumors had a significantly higher risk of HNCSM (P<.001), SPCM (P<.001), and NCCM (P<.001) than those with HPV-negative tumors.
HPV-positive OPSCC has a lower NCSM, SPCM, and NCCM as compared to those with HPV-negative OPSCC. HPV positivity is a favorable prognostic factor in the context of overcoming cancer as well as in terms of reducing the risk of other CODs in OPSCC. Our finding supports the need to tailor patient follow-up based on the HPV status of patients with OPSCC.

Oropharyngeal carcinoma is one of the most common malignant tumors of head and neck. In recent years, the incidence of Human papilloma virus-associated oropharyngeal squamous cell carcinoma（HPV-OPSCC） has been increasing year by year. With the advancement of minimally invasive surgical techniques, the wide application of intensity modulated radiation therapy, and the demand of patients for organ function protection and higher quality of life, the unique biological behavior and better prognosis of HPV-OPSCC have led to the exploration of a series of attenuated treatment modes. This article reviews the diagnosis and treatment status of oropharyngeal cancer and related research progress based on relevant reports.
摘要: 口咽癌是常见的头颈部恶性肿瘤之一。近年来，人乳头状瘤病毒相关性口咽鳞状细胞癌（human papilloma virus-associated oropharyngeal squamous cell carcinoma，HPV-OPSCC）发病率呈逐年上升趋势。随着外科微创手术技术的进步、调强放射治疗的广泛应用，以及患者对器官功能保护和更高生活质量的需求，HPV-OPSCC独特的生物学行为和较好的预后引发了一系列减毒治疗模式的探索。现结合相关报道就口咽癌诊疗现状及相关研究进展做一综述。.

Objective:To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor. Methods:A retrospective analysis was performed on 468 pathologically confirmed oropharyngeal cancer as the primary tumor patients with p16 status, excluded distant metastasis, and admitted to the Chinese Academy of Medical Sciences from January 2010 to December 2020. The clinical features and prognosis of the secondary primary tumor were analyzed. Results:Among 468 patients with oropharyngeal cancer treated at initial diagnosed, 222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6%（42/66） were synchronous and 36.4%（24/66） were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2%（P=0.001）; The second primary cancer accounted for 11.2%（12/107） of the deaths in the whole group, among them, the heterochronous second primary accounted for 75.0%（9/12）. There were 246 patients with p16 positive, with a median follow-up time of 52.4 months, 20 patients developed second primary cancer（8.1%）. Among them, 65.0%（13/20） were synchronous and 35.0%（7/20） were heterochronous. Esophagus was the most commonly involved site. The 4-year OS of p16-positive with synchronous, heterochronous and non-second primary cancer group were 51.9%, 80.7% and 83.3%. Secondary primary cancer accounted for 3.8%（2/52） of all deaths in p16 positvie group. Conclusion:The incidence of second primary cancer of p16 positive and negative oropharyngeal carcinoma were different. The esophagus was the most commonly involved site regardless of p16 status. Regardless of p16 status, the survival of patients with synchronous second primary cancer was worse than those without second primary cancer. For p16-negative oropharyngeal carcinoma, the prognosis was better in patients with heterogeneous second primary cancer, the second primary cancer is one of the main causes of death.
目的：在真实世界中分析口咽癌合并第二原发肿瘤的临床特征及预后。 方法：回顾性分析2010年1月至2020年12月中国医学科学院肿瘤医院收治的468例经病理证实，排除远转移，明确p16状态的以口咽为首发肿瘤的患者，分析合并第二原发肿瘤的临床特征及预后。 结果：468例初治口咽癌患者，其中p16阴性222例，中位随访时间64.3个月，66例（29.3%）发生第二原发癌，其中42例（63.6%）为同时性，24例（36.4%）为异时性，食管为最常见累及部位，p16阴性口咽癌合并同时性第二原发癌、异时性第二原发癌组和无第二原发癌3组的5年生存率（overall survival OS）分别为26.3%，57.3%和73.2%（P=0.001）；第二原发癌占全组死因的11.2%（12/107），其中异时性第二原发占75.0%（9/12）。p16阳性246例，中位随访时间52.4个月，20例（8.1%）发生了第二原发癌，其中13例（65.0%）为同时性，7例（35.0%）为异时性，食管为最常见累及部位，p16阳性同时性第二原发癌组和不合并第二原发癌组4年OS分别为51.9% vs 80.7%（P=0.006）；p16阳性同时性第二原发癌组和合并异时性第二原发癌组4年OS分别51.9% vs 83.3%（P=0.068）。第二原发癌占全组死因的3.8%（2/52）。 结论：p16阴性口咽癌发生第二原发癌概率高于p16阳性患者。无论p16状态，合并同时性第二原发癌的生存差于不合并第二原发癌组；食管均为最常见累及部位；p16阴性口咽癌，合并异时性第二原发癌预后较好，第二原发癌是其主要死因之一。.

In recent years, the incidence of oropharyngeal carcinoma （OPC） is increasing, while the better prognosis of patients with Human papillomavirus （HPV） positive oropharyngeal carcinoma has been confirmed in a number of studies. There are a variety of detection methods for HPV-associated oropharyngeal carcinoma. Including P16 immunohistochemistry, Polymerase Chain Reaction （PCR） or In situ hybridization （ISH） detection of HPV DNA, HPV RNA, Revers transcriptase Polymerase Chain Reaction （RT PCR） was used to detect HPV RNA. The better prognosis of patients with HPV-positive oropharyngeal carcinoma has led to the emergence of a large number of degraded treatment trials. The traditional P16 test has certain limitations in the diagnosis of patients with HPV-positive oropharyngeal carcinoma. It is necessary to combine with other detection methods to accurately screen out patients with HPV-positive oropharyngeal carcinoma and better apply to degraded therapy. In this article, we will briefly introduce the trend of HPV-associated oropharyngeal carcinoma, the detection methods and the new progress of degraded treatment trials.
摘要: 近年来，口咽癌（OPC）的发病率不断增加，人乳头状瘤病毒（HPV）阳性OPC患者的预后更好已在多项研究中得到证实。HPV相关OPC有多种检测方法，包括P16免疫组织化学、聚合酶链式反应法或原位杂交法（in situ hybridization，ISH）检测HPV DNA、HPV RNA，逆转录酶聚合酶链式反应法检测HPV RNA。HPV阳性OPC患者良好的预后导致大量降级治疗试验的出现，传统的P16检测确诊的HPV阳性OPC患者存在一定的局限性，需要结合其他检测方法准确地筛选，更好地适用于降级治疗。本文对HPV相关OPC的发病趋势、检测方法及降级治疗试验的新进展进行综述。.

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug-induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)-negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF-κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV-negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV-negative patients than radiosensitive HPV-negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased DNA double-strand break (DSB) and radiation-induced apoptosis, thereby increasing the radiosensitivity of HPV-negative oropharyngeal carcinoma cells. IRE1-XBP1 silencing also inhibited radiation-induced IL-6 expression at both the RNA and protein levels. The regulatory effect of IRE1-XBP1 silencing on DNA DSB-induced and radiation-induced apoptosis was inhibited by pretreatment with IL-6. These data indicate that IRE1 regulates radioresistance in HPV-negative oropharyngeal carcinoma through IL-6 activation, enhancing X-ray-induced DNA DSB and cell apoptosis.

The activation of epidermal growth factor receptor (EGFR) is associated with radioresistance in malignant tumors. Specifically, radiation can destroy endoplasmic reticulum (ER) homeostasis to induce ER stress (ERS). However, the effect of EGFR-mediated regulation of ERS signaling pathway on radiosensitivity has not yet been reported. The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK-eIF2α-GRP94 and IRE1α-XBP1-GRP78). This effect was abolished by pretreatment with EGF, however. In addition, knockdown of EGFR in OSCC cells inhibited DNA double-stand break repair and autophagy while increased radiation-induced apoptosis. Conversely, activating ERS inhibited the aforementioned functions. Furthermore, EGF increased ER stress-independent ERK and AKT signaling upon irradiation of OSCC cells. Immunohistochemical analysis of 80 tissue samples from OSCC patients showed that co-expression of EGFR and PERK was associated with poor prognosis. It thus appears EGFR confers radioresistance in OSCC by activating ER stress signaling. These results suggested that the cooperative effects of radiotherapy and EGFR-targeted inhibitor therapy can be further improved by inhibiting PERK-eIF2α-GRP94 and IRE1α-GRP78 in non-response oropharyngeal carcinoma patients.

Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis and development of malignant tumors, as well as in the regulation of radiochemoresistance and chemoresistance in many malignancies. ERS signaling pathway protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2 (eIF2α) may induce aberrant activation of nuclear factor-κB (NF-κB). Our previous study showed that NF-κB conferred radioresistance in lymphoma cells. However, whether PERK-eIF2α regulates radioresistance in oropharyngeal carcinoma through NF-κB activation is unknown. Herein, we showed that PERK overexpression correlated with a poor prognosis for patients with oropharyngeal carcinoma (P < 0.01). Meanwhile, the percentage of the high expression level of PERK in oropharyngeal carcinoma patients resistant to radiation was higher than in patients sensitive to radiation (77.7 and 33.3%, respectively; P < 0.05). Silencing PERK and eIF2α increased the radiosensitivity in oropharyngeal carcinoma cells and increased radiation-induced apoptosis and G2/M phase arrest. PERK-eIF2α silencing also inhibited radiation-induced NF-κB phosphorylation and increased the DNA double strand break-related proteins ATM phosphorylation. NF-κB activator TNF-α and the ATM inhibitor Ku55933 offset the regulatory effect of eIF2α on the expression of radiation-induced cell apoptosis-related proteins and the G2/M phase arrest-related proteins. These data indicate that PERK regulates radioresistance in oropharyngeal carcinoma through NF-kB activation-mediated phosphorylation of eIF2α, enhancing X-ray-induced activation of DNA DSB repair, cell apoptosis inhibition and G2/M cell cycle arrest.