Zhiyong Liang

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

Background Lung adenocarcinoma (AD) is a common variant of non-small cell lung cancer (NSCLC). Programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) are promising immunotherapy targets and its expression may be an important biomarker of predicting clinical response. In this study, we evaluated PD-L1 expression in conjunction with clinicopathological characteristics and outcomes in resected lung adenocarcinoma. Results This study included 133 cases of lung adenocarcinoma. PD-L1 expression rate in lung adenocarcinoma was 16.5% at the mRNA level and 13.5% at the protein level, and the kappa coefficient of the two examination methods was 0.824 (P = 0.219, highly correlated). PD-L1 was highly expressed in male patients and smokers with lung adenocarcinoma (P = 0.019 and 0.002, respectively), while no associations were identified between PD-L1 expression and age, tumor size, clinical stage, positive pleural invasion, lymph node metastasis, or therapy methods. Overexpression of PD-L1 was a significant indicator of shorter recurrence free survival time and overall survival (P = 0.000 and 0.000, respectively). Multivariate analysis revealed that PD-L1 expression was an independent risk factor for poor recurrence free survival and overall survival (P = 0.009 and 0.016, respectively). Materials and Methods Expression of PD-L1 was examined with immunohistochemistry, using the VENTANA PD-L1 (SP263) rabbit monoclonal antibody. mRNA levels of PD-L1 were evaluated using in situ hybridization. Conclusions PD-L1 overexpression is more frequently observed in male patients and smokers in lung adenocarcinoma. PD-L1 expression is an indicator of worse prognosis in surgically resected lung adenocarcinoma patients.

CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer

Chemokine (C-X-C motif) receptor 7 (CXCR7) and its ligand, chemokine (C-X-C motif) ligand 12 (CXCL12), were established to be involved in biological behaviors and associated with prognosis in many cancers. However, effects, underlying mechanisms of CXCL12-CXCR7 axis in invasive phenotype of pancreatic cancer (PC) and its clinicopathologic significances have not been comprehensively explored. In the present study, it was first found by tissue microarray-based immunohistochemistry that CXCL12 and CXCR7 staining scores were significantly associated with vessel invasion and overall survival in two independent cohorts of PC. Besides, co-expression of these proteins was an independent prognosticator in multivariate analysis in both cohorts. Then, migration and invasion, but not proliferation, were decreased in CXCR7-stably silenced PC cells, whereas opposite changes were observed in CXCR7-stably overexpressed cells, accompanied by alterations of mTOR and Rho/ROCK pathways. CXCL12 stimulated migration, invasion, CXCR7 expression and phosphorylation of key mTOR proteins. AMD3100 did not influence effects of CXCL12. Two mTOR inhibitors, rapamycin and Torin1, reversed enhanced invasive phenotypes and mTOR phosphorylation in CXCR7-overexpressed cells. Moreover, CXCR7 directly interacts with mTOR. Finally, liver metastasis, but not growth, was affected by CXCR7 status in orthotopically-implanted PC models in nude mice. Collectively, CXCL12-CXCR7 axis accelerates migration and invasion of PC cells through mTOR and Rho/ROCK pathways, and predicts poor prognosis of PC.

Hobnail variant of papillary thyroid carcinoma: molecular profiling and comparison to classical papillary thyroid carcinoma, poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma

Background As a rare but aggressive papillary thyroid carcinoma (PTC) variant, the genetic changes of hobnail variant of PTC (HVPTC) are still unclear. Results The prevalence of HVPTC was 1.69% (18/1062) of all PTC diagnosed in our cohort. 73 samples from 55 patients (17 HVPTC, 26 CPTC, 7 PDTC and 5 ATC) were successfully analyzed using targeted NGS with an 18-gene panel. Thirty-seven mutation variant types were identified among 11 genes. BRAF V600E mutation was the most common mutation, which is present in almost all HVPTC samples (16/17, 94%), most CPTC samples (20/26, 77%), and none of the ATC and PDTC samples. TERT promoter mutation (C228T) was identified in 2 ATC and one HVPTC patient. RAS and TP53 mutation are almost exclusively present among ATC and PDTC samples although TP53 mutation was also observed in 3 HVPTC patients. Six different GNAS mutations were identified among 8 CPTC patients (31%) and none of the HVPTC patients. The only patient who died of disease progression harbored concomitant TERT C228T mutation, BRAF V600E mutation and TP53 mutation. Methods HVPTC cases were identified from a group of 1062 consecutive surgical specimens diagnosed as PTC between 2000 and 2010. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of HVPTC, compared to classical PTC (CPTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Conclusion As an aggressive variant of PTC, HVPTC has relatively specific molecular features, which is somewhat different from both CPTC and ATC/PDTC and may underlie its relatively aggressive behavior.

EGFR T790M ctDNA testing platforms and their role as companion diagnostics: Correlation with clinical outcomes to EGFR-TKIs.

Somatic mutation in the epidermal growth factor receptor (EGFR) predict clinical response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and is a promising target for personalised medicine. EGFR mutations have prognostic value. Initially patients respond well to tyrosine kinase inhibitors but finally they would develop resistance and about 50% of this resistance can be attributed to the emergence of EGFR resistant mutation, T790M. This necessitates the need for genetic testing for clinical management of patients. Molecular testing has become the standard of care in patients with NSCLCs based on the recommendations of standard guidelines. Though there are several platforms for EGFR mutation detection, highly sensitive platforms for clinical applicability as companion diagnostics for ctDNA based testing are emerging. Due to the dynamic changes in the T790M mutation during tyrosine kinase inhibitor (TKI) treatment, real-time monitoring of these genetic alterations is mandate for planning treatment strategies. With the advent of third generation TKIs that potentially target T790M, improvement in clinical outcome is documented in patients with NSCLCs. Managing these outcomes with appropriate companion diagnostics using ctDNA in early detection of these genetic alterations will improve patient care.

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

Phosphorylation is a recently established cause of phosphatase and tensin homolog (PTEN) gene inactivation, which leads to defect tumour-suppressor function. In pancreatic cancer, this phenomenon has not been reported. Based on database and clinical sample analyses, we found that PTEN phosphorylation occurs in pancreatic ductal adenocarcinoma patient tissues and cell lines, and we aimed to find a method for dephosphorylation. PDZ-containing 1 (PDZK1), a tumour-associated protein that shares its PDZ-binding sequence with the carboxyl-terminal domain of PTEN, was significantly down-regulated in pancreatic cancer as compared to adjacent non-tumour tissues. In vitro, PDZK1 overexpression reversed the proliferation and migration abilities of pancreatic cancer cells and led to significantly decreased PTEN phosphorylation and AKT phosphorylation by interacting with wild-type PTEN. In addition, a transcription factor-activation assay supported that PDZK1 overexpression enhanced the anti-oncogene function of PTEN by regulating the activities of its downstream transcription factors, including p53, NF-κB, and FOXO1. In vivo, nude mice stably over-expressing PDZK1 had lower tumour weights and volumes and showed significantly down-regulated PTEN phosphorylation in xenograft tumour tissues as compared to the control group. Moreover, low PDZK1 expression strongly correlated with advanced stage and poor prognosis of patients with pancreatic ductal adenocarcinoma. In conclusion, our study elucidated the tumour-suppressor role of PDZK1 in pancreatic cancer through down-regulating PTEN phosphorylation, and established PDZK1 as a potential novel prognostic marker for pancreatic cancer.

Gallbladder papillary neoplasms share pathological features with intraductal papillary neoplasm of the bile duct

Intraductal papillary neoplasm of the bile duct (IPNB) has been widely recognized. However, the knowledge of intracystic papillary neoplasm of the gallbladder (IPNG) including papillary adenoma and adenocarcinoma is not well defined. In this study, we compared the clinicopathological and immunohistochemical features between 32 IPNG cases and 32 IPNB cases. IPNG-1 (low-high grade dysplasia) exhibited an earlier onset age, smaller tumor size and lower level of CK20 expression compared to IPNG-2 (invasive carcinoma). Histologically, pancreaticobiliary and intestinal subtype accounted for nearly half of IPNG or IPNB (44.4% and 48.1% vs. 44.0% and 44.0%), respectively. Immunohistochemically, 88.9% of IPNG and 92.0% of IPNB cases were positive for MUC1, and 96.3% and 92.0% for CK7, respectively. CDX2 and MUC2 were more highly expressed in the intestinal subtype than in other subtypes. CK20 expression increased in parallel with tumor progression. In addition, 53.1% of IPNG cases and 68.6% of IPNB cases exhibited invasive carcinoma, and showed significant survival advantages to conventional gallbladder adenocarcinoma and cholangiocarcinoma, respectively. In conclusion, papillary adenoma and adenocarcinoma of the gallbladder can be recognized as different pathological stages of IPNG, and they share pathological features with IPNB.

Expression of key mTOR pathway components in pancreatic ductal adenocarcinoma: A multicenter study for clinicopathologic and prognostic significance

Thus far, clinicopathologic and prognostic significance of mTOR signaling pathway in pancreatic ductal adenocarcinoma (PDAC) remains unclear, although it is involved in PDAC. In this study, total (t-) and phosphorylated (p-) mTOR, 4EBP1 and P70S6K, were investigated. It was found that most aforementioned proteins were related to malignant and progressive phenotypes, especially histological grade, in independent development and validation cohorts of PDAC. In the development cohort, high expression and/or phosphorylation of mTOR, 4EBP1 and P70S6K were all univariately associated with poor tumor-specific survival, whereas p-mTOR, p-4EBP1 and p-P70S6K, adjusted for clinicopathologic variables, unlike t-mTOR, t-4EBP1 and t-P70S6K, were shown to be independent prognostic factors in multivariate analysis. Interestingly and importantly, the independently significant impacts of p-mTOR and p-4EBP1 on tumor-specific survival were confirmed in the validation cohort. Contrarily, t-mTOR and t-4EBP1 were only univariately significant, while t-P70S6K and p-P70S6K were not prognostic. Finally, mTOR and EIF4EBP1, genes encoding mTOR and 4EBP1, also serve as prognostic indicators in the publicly available TCGA RNA-sequencing database. Our data indicate that expression and activation, especially the latter, of mTOR and 4EBP1, might have clinicopathologic and prognostic significance in PDAC.

Clinicopathological analysis of Large Cell Lung Carcinomas definitely diagnosed according to the New World Health Organization Criteria

OBJECTIVE The definition of large cell lung carcinoma (LCC) has undergone an extensive modification in the World Health Organization (WHO) Classification (2015). Present study aimed to investigate the clinicopathological characteristics of patients diagnosed as LCC according to current WHO criteria. METHODS LCCs diagnosed based on the previous WHO classification were reevaluated, and 17 cases of LCC were finally identified at Peking Union Medical College Hospital and Beijing Chest Hospital between 2009 and 2015. The clinicopathologic features were examined and EGFR and KRAS mutations were tested. Survival of the patients was analyzed by Kaplan-Meier method. RESULTS The median age of the patients was 64 years (range: 40-78). Most patients were male (64.7%) and about half of the patients were at TNM stage III (47.1%). Morphologically, most cases (70.6%) were classic LCC. All patients were treated by lobectomy plus lymph node dissection, 2 with bi-lobectomy and 1 with complex lobectomy, and the other 2 patients were further treated by partial pericardiotomy. Ten patients received postoperative chemotherapy, while only 3 patients were treated with radiotherapy after surgery. Molecular analysis showed two cases of EGFR mutation (L858R) but without non-overlapping KRAS mutation. The 3-year overall survival rate was 48.4 ± 15.1%. Chemotherapy was the only predictive factor that is associated with the prognosis of the patients (P = 0.003). CONCLUSION The clinicopathological characteristics of 17 cases of stringently diagnosed LCC were retrospectively analyzed. LCC in our study showed aggressive behavior with high recurrence and metastasis and poor prognosis. Chemotherapy was only predictive factor that is significantly associated with the prognosis of the patients. Future studies based on a larger series and long term follow-up are still needed to characterize it further.

Retraction: PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

[This retracts the article DOI: 10.18632/oncotarget.20552.].

Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207

Gemcitabine serves as a first‐line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well‐established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non‐protein coding) (PVT1) has been reported to be an oncogenic long non‐coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased cell growth in PC cells treated with gemcitabine. We also demonstrate that gemcitabine treatment decreases PVT1 levels and increases its encoded miRNAs, such as the miR‐1207 pair (miR‐1207‐5p/3p). Overexpression of the miR‐1207 pair enhanced the chemosensitivity of cells to gemcitabine, whereas silencing of miR‐1207‐5p/3p to prevent its induction by gemcitabine treatment led to increased cell growth. Mechanistic studies revealed that miR‐1207‐5p and miR‐1207‐3p target the SRC proto‐oncogene (non‐receptor tyrosine kinase) and ras homolog family member A in PC cells, respectively. In particular, we observed that gemcitabine induced Drosha ribonuclease III (Drosha) and DGCR8 microprocessor complex subunit (DGCR8) upregulation and then triggered PVT1 processing. Suppression of Drosha and DGCR8 contributed to a dampened efficacy of gemcitabine, indicating that gemcitabine decreased PVT1 expression by promoting its processing into miRNAs, which in turn resulted in blunted oncogenic signaling in PC cells. Moreover, we demonstrate that gemcitabine chemoresistance was a result of decreased expression of Drosha and DGCR8 in AsPC‐1 cells and tumor cell‐engrafted models. Overall, our findings define a novel mechanism for understanding the efficacy of gemcitabine chemotherapy in PC.