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Background Thyroid hemiagenesis (THA) is a rare abnormality featured by the absence of one thyroid lobe, and there have been no reports of using endoscopic thyroidectomy to treat papillary thyroid carcinoma with THA. Case presentation A case of THA with a missing right lobe was reported. Ultrasonography revealed a Thyroid Imaging, Reporting and Data System (TI-RADS) 5 lesion on the thyroid. The patient underwent a gasless transaxillary endoscopic thyroidectomy (GTET) during which it was discovered that the thyroid gland was located on the opposite side and that there were anatomic malformations present. While GTET contributes to clear vision during surgery and excellent postsurgical appearance, lateral forces produced by the retractor may dislocate tissues, obscuring the targeted thyroid, thus increasing the operative difficulties. Conclusions Transaxillary endoscopic surgical strategy is not overall superior to conventional approach and should be chosen consciously.

Anaplastic thyroid carcinoma (ATC) is a rare and extremely aggressive type of thyroid cancer, and the potential mechanisms involved in ATC progression remains unclarified. In this study, we found that forkhead box K2 (FOXK2) was upregulated in ATC tissues, and the expression of FOXK2 was associated with tumor size. Evidenced by RNA-seq and Chromatin immunoprecipitation (ChIP)-seq assays, FOXK2 positively regulated VEGF and VEGFR signaling network, among which only VEGFA could be noticed in both RNA-seq and ChIP-seq results. ChIP, dual-luciferase reporter system and functional experiments further confirmed that FOXK2 promoted angiogenesis by inducing the transcription of VEGFA. On VEGFR2 blockage by specific targeting agent, such as Apatinib, FOXK2 could rapidly trigger therapeutic resistance. Mechanical analyses revealed that VEGFA transcriptionally induced by FOXK2 could bind to VEGFR1 as a compensation for VEGFR2 blockage, which promoted angiogenesis by activating ERK, PI3K/AKT and P38/MAPK signaling in human umbilical vein endothelial cells (HUVECs). Synergic effect on anti-angiogenesis could be observed when VEGFR1 suppressor AF321 was included in VEGFR2 inhibition system, which clarified the pivot role of FOXK2 in VEGFR2 targeting therapy resistance. More importantly, the binding of VEGFA to VEGFR1 could further promoter FOXK2-mediated VEGFA transcription, which consequently constituted a positive feedback loop. Therefore, the novel loop VEGFA/VEGFR1/FOXK2 functioned importantly in resistance to VEGFR2 targeting therapy in FOXK2+ ATCs. Altogether, FOXK2 plays critical roles in ATC angiogenesis and VEGFR2 blockage resistance by inducing VEGFA transcription. FOXK2 represents a potentially new therapeutic strategy and biomarker for anti-angiogenic therapy against ATC.

Background Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated. Methods Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro. Results Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network. Conclusions The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.

Background Although a substantial increase in the survival of patients with other cancers has been observed in recent decades, pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases. No effective screening approach exists. Methods Differential exosomal long noncoding RNAs (lncRNAs) isolated from the serum of patients with PDAC and healthy individuals were profiled to screen for potential markers in liquid biopsies. The functions of LINC00623 in PDAC cell proliferation, migration and invasion were confirmed through in vivo and in vitro assays. RNA pulldown, RNA immunoprecipitation (RIP) and coimmunoprecipitation (Co-IP) assays and rescue experiments were performed to explore the molecular mechanisms of the LINC00623/NAT10 signaling axis in PDAC progression. Results A novel lncRNA, LINC00623, was identified, and its diagnostic value was confirmed, as it could discriminate patients with PDAC from patients with benign pancreatic neoplasms and healthy individuals. Moreover, LINC00623 was shown to promote the tumorigenicity and migratory capacity of PDAC cells in vitro and in vivo. Mechanistically, LINC00623 bound to N-acetyltransferase 10 (NAT10) and blocked its ubiquitination-dependent degradation by recruiting the deubiquitinase USP39. As a key regulator of N4-acetylcytidine (ac4C) modification of mRNA, NAT10 was demonstrated to maintain the stability of oncogenic mRNAs and promote their translation efficiency through ac4C modification. Conclusions Our data revealed the role of LINC00623/NAT10 signaling axis in PDAC progression, showing that it is a potential biomarker and therapeutic target for PDAC.

Due to technical challenges, single-site endoscopic thyroidectomy (SSET) is seldom reported and has been attempted in only limited cases. This large-scale study aimed to compare the clinical outcomes of standardized transareola SSET (TASSET) with those of conventional open thyroidectomy (COT) for thyroid cancer. The data were prospectively collected, and case-match study was performed at a ratio of 1:1 according to age, sex, body mass index, lesion size, number of lesion foci, lesion side, recurrent laryngeal nerve (RLN) exploration and pathology. Two hundred eligible patients underwent TASSET, and the same number of patients was selected for propensity score matching from 2256 patients who underwent COT. Perioperative data, including surgical profile, oncological and traumatic burdens, and cosmetic satisfaction, were analyzed. No significant differences were observed in blood loss or drainage between TASSET and COT groups. There were no differences in operation time between TASSET and COT (106.39 ± 28.44 vs 102.55 ± 23.10 min, p = 0.154). A total of 3.63 ± 1.82 lymph nodes (LNs) were retrieved from CND with 0.96 ± 1.42 positive in TASSET. In COT, the total and positive LN yields were 3.77 ± 1.91 and 0.99 ± 1.40 (p = 0.445, p = 0.802). Cancer recurrence was not observed in either group. There were no differences in the occurrence of permanent and transient hoarseness or RLN injuries. Postoperative flap seroma or hematoma occurred in 12 TASSET patients and 58 COT patients (p

ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-β/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.

Overexpression of fibroblast growth factor receptor 3 (FGFR3) correlates with more severe clinical features of hepatocellular carcinoma (HCC). Our previous study has shown that FGFR3∆7–9, a novel splicing mutation of FGFR3, contributes significantly to HCC malignant character, but the epigenetic mechanism is still elusive. In this study, through mass spectrometry and co-immunoprecipitation studies, we discover a close association between FGFR3∆7–9 and the DNA demethylase Ten-Eleven Translocation-2 (TET2). Unlike other certain types of cancer, mutation of TET2 is rare in HCC. However, activation of FGFR3∆7–9 by FGF1 dramatically shortens TET2 half-life. FGFR3∆7–9, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2. Overexpression of a phospho-deficient mutant TET2 (Y1902F) significantly reduces the oncogenic potential of FGFR3∆7–9 in vitro and in vivo. Furthermore, FGFR3∆7–9 significantly enhances HCC cell proliferation through the TET2-PTEN-AKT pathway. Specifically, TET2 offsets the elevation of p-AKT level induced by FGFR3∆7–9 through directly binding to PTEN promoter and increasing 5-hmC. Therefore, through phosphorylation and inhibition of TET2, FGFR3∆7–9 reduces PTEN expression and substantiates AKT activation to stimulate HCC proliferation. Together, this study identifies TET2 as a key regulator of the oncogenic role of FGFR3∆7–9 in HCC carcinogenesis and sheds light on new therapeutic strategies for HCC treatment.

In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC.

Background ETV5 mediated angiogenesis was dependent on PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC) in our previous study. However, whether ETV5 affects effect of antiangiogenic therapy in CRC requires further investigation. Methods GSEA analysis and a series of experiments were performed to identify the critical candidate gene involved in bevacizumab resistance, and further explored whether the treatment targeting the candidate gene enhanced bevacizumab sensitivity in vitro and in vivo. Results ETV5 could directly bind to VEGFA promoter and promote translation of VEGFA. However, by in vitro and in vivo experiments, ETV5 actually accelerated anti-VEGF therapy (bevacizumab) resistance. GSEA analysis and further assays confirmed that ETV5 could promote angiogenesis by enhancing secretion of another tumor angiogenesis factor CCL2 in CRC cells, which resulted in bevacizumab resistance. ETV5 induced VEGFA and CCL2 were mutually independent to induce angiogenesis by activating PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells. In CRC tissues, ETV5 protein level was positively associated with CD31, CCL2, VEGFA protein expression. CRC patients with high expression of ETV5/VEGFA or ETV5/CCL2 showed inferior prognosis than other patients. Combination of anti-CCL2 and anti-VEGFA (Bevacizumab) treatment could more effectively inhibited tumor angiogenesis and growth than single treatment did in CRCs with high expression of ETV5 (ETV5 + CRCs). Conclusions Our results not only revealed ETV5 as a novel biomarker for antiangiogenic therapy, but also indicated a potential combined therapy strategy by simultaneously targeting CCL2 and VEGFA in ETV5 + CRC.

As an established anticancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose‐dependent manner in PANC‐1 and BxPC‐3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM‐induced cytotoxicity, and CQ was more effective than ATG7 siRNA. Moreover, CQ significantly enhanced GEM‐induced apoptosis, while ATG7 siRNA failed to show the similar effect. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that GEM with CQ pretreatment markedly triggered reactive oxygen species (ROS) boost and then increased lysosomal membrane permeability. Consequently, cathepsins released from lysosome into the cytoplasm induced apoptosis. We showed that CQ could enhance PC cells response to GEM in xenograft models. In conclusion, our data showed that CQ sensitized PC cells to GEM through the lysosomal apoptotic pathway via ROS. Thus, CQ as a potential adjuvant to GEM might represent an attractive therapeutic strategy for PC treatment.

Background: Our previous study has shown that FGFR3∆7-9, a novel splicing mutation of FGFR3, contributes significantly to hepatocellular carcinoma (HCC) malignancy. However, the functional roles of oncogenic FGFR3∆7-9 are far more clear. In this study, we aimed to understanding regulatory mechanism, signaling, and clinical role of FGFR3∆7-9 in HCC carcinogenesis. Methods: Mass spectrometry and co-immunoprecipitation were employed to identify the interactors with FGFR3∆7-9. The expression and biological functions of DNA demethylase Ten-Eleven Translocation-2 (TET2) were detected in vivo and in vitro. The binding and tyrosine phosphorylation sites of TET2 to FGFR3∆7-9 were pinpointed structurally and functionally. Mechanism of TET2 in modulating PTEN expression was examined by chromatin immunoprecipitationassays and Methylation-Sensitive qPCR. Findings: It is the amount of TET2 rather than mutation functions more importantly in carcinogenesis. Downregulation of TET2 positively correlated with the poorer prognosis of HCC. TET2 could directly interact with FGFR3∆7-9 and phosphorylated at Y1902, which was the solo tyrosine phosphorylation site in the key binding fragment to FGFR3∆7-9. Phospho-deficient mutant TET2 (Y1902F) significantly reduced the tumorigenesis potential of FGFR3∆7-9 in vitro and in vivo. Through the ubiquitination and proteosomal degradation of TET2, FGFR3∆7-9 reduced PTEN expression, and then rescued the level of p-AKT to trigger the HCC cell growth advantage. Interpretation: The novel link between FGFR3∆7-9 and TET2 revealed the important functional roles of oncogenic FGFR3∆7-9 in HCC. FGFR3△7-9 promotes HCC progression via the phosphorylation and destabilization of TET2. Targeting the FGFR3△7-9/TET2-PTEN-AKT signaling axis may contribute to develop new therapeutic strategies for HCC treatment. Funding Statement: This work was supported by the following grants: National Natural Science Foundation of China (NSFC: 81772558), Shanghai Charity Research Foundation of Cancer Research, China Scholarship Council (201906230139), Ph.D. Innovation Fund of Shanghai Jiaotong University School of Medicine (BXJ201709), and “Visiting Programs for Graduate Students of Shanghai Jiaotong University School of Medicine” for this study. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Written informed consent was obtained and the research was approved by the local Ethics Committee and the Institutional Review Board. All patients were fully informed of the experimental procedures and were made aware of the potential risks and complications of the proposed treatment scheme. All animal studies were approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

Background The extent of total thyroidectomy in the management of multinodular goiter remains unclear. Compared to primary thyroidectomy, secondary total thyroidectomy is more difficult to perform and carries a significantly higher risk of postoperative complications such as recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism. In this study, we aimed to evaluate the efficacy and safety of intraoperative carbon nanoparticle (CN) mapping in patients undergoing secondary total thyroidectomy. Methods We performed a case-matched analysis of a prospectively maintained database using 8 specific criteria to compare perioperative outcomes after primary total thyroidectomy to those after secondary total thyroidectomy with intraoperative CN mapping. The criteria included age, sex, operative procedure, RLN/parathyroid glands (PGs) exploration, preoperative vocal cord calcium abnormalities, and pathological results. Thirty-five patients underwent secondary total thyroidectomy with intraoperative CN mapping due to recurrent thyroid nodules or development of nodules suspicious for malignancy after subtotal thyroidectomy. Fifty exact matches for all 8 criteria were identified from the database in our previous study, which included records of 3078 primary thyroidectomies without CNs. Perioperative outcomes, surgical technique, and complications were analyzed. Results The RLNs were successfully identified in all 35 patients. Among three patients that experienced slight hoarseness, one had an RLN end-to-end anastomosis with subsequent improvement in the during the 12-month follow-up period. Two patients experienced changes in vocal tone, but recovered after several months. Two patients underwent parathyroid auto-transplantations, and subsequently presented with transient hypocalcaemia. Their symptoms gradually remitted within one year. Except for mean operation time, there were no statistically significant differences in complications between the primary total thyroidectomies and the secondary total thyroidectomy with CNs. Conclusions Intraoperative CN mapping, expert knowledge of the jugular anatomy, and standardized resection procedures can minimize the incidence of complications such as RLN palsy and hypoparathyroidism after secondary total thyroidectomy.

Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, has been shown to promote anti-cancer action across a wide range of malignancies, including gastric, lung, and breast cancers. Our previous study showed that apatinib increases apoptosis in anaplastic thyroid carcinoma (ATC), but the direct functional mechanism of tumor lethality mediated by apatinib is still unknown. In this study, we demonstrated that apatinib induced both autophagy and apoptosis in human ATC cells through downregulation of p-AKT and p-mTOR signals via the AKT/mTOR pathway. Moreover, inhibition of apatinib-induced autophagy increased apatinib-induced apoptosis in ATC cells, and additional tumor suppression was critically produced by the combination of apatinib and the autophagy inhibitor chloroquine in vivo and in vitro. These findings showed that both autophagy and AKT/mTOR signals were engaged in ATC cell death evoked by apatinib. ATC patients might benefit from the new anti-cancer drug, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.