Porphyromonas gingivalis promotes progression of esophageal squamous cell cancer via TGFß-dependent Smad/YAP/TAZ signaling.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

Complete genome sequences of three Porphyromonas gingivalis strains, isolated from patient with esophageal squamous cell carcinoma and healthy individual in China.

Here, we report the complete genome sequences of three Porphyromonas gingivalis, one from patient with esophageal cancer (LyEC01), and the other two from periodontally healthy individuals (LyG-1 and LyG-2) in 2021 and 2023. The genome sizes of LyEC01, LyG-1, and LyG-2 were 2,408,275, 2,411,440, and 2,411,481 bp, respectively.

Retrospective analysis of Porphyromonas gingivalis in patients with nasopharyngeal carcinoma in central China.

Little is known about the presence and possible role of Porphyromonas gingivalis (P. gingivalis) in nasopharyngeal carcinoma (NPC), its co-infection with Epstein-Barr virus (EBV), or their association with clinical characteristics of patients with NPC in Central China, where NPC is non-endemic. A total of 45 NPC formalin-fixed paraffin-embedded (FFPE) tissues were retrospectively analyzed using immunohistochemistry (IHC) and a nested PCR combined with DNA sequencing to detect the presence of P. gingivalis, and using reverse transcription-quantitative PCR to detect the presence of EBV. Clinical data including EBV and P. gingivalis status were associated with overall survival (OS). All tumors were undifferentiated, non-keratinizing carcinomas, of which 40/45 (88.9%) were positive for EBV (EBV+), 26/45 (57.8%) were positive for P. gingivalis (by IHC), and 7/45 (15.6%) were positive for P. gingivalis DNA (P. gingivalis +). All seven P. gingivalis DNA-positive NPCs were co-infected with EBV. The 5-year survival rates of the patients with EBV-/P. gingivalis -, EBV+/P. gingivalis -, and EBV+/P. gingivalis + tumors were 60.0% (3/5), 39.4% (13/33) and 42.9% (3/7), respectively. No significant difference was found between the OS of NPC patients among the different infection groups (P=0.793). In conclusion, to the best of our knowledge, this is the first study to describe and confirm the presence of P. gingivalis in FFPE tissues from patients with NPC. P. gingivalis was found to co-exist with EBV in NPC tumor tissues, but is not etiologically relevant to NPC in non-endemic areas, such as Central China.

Selective activation of TGFß signaling by P. gingivalis-mediated upregulation of GARP aggravates esophageal squamous cell carcinoma.

Aberrant TGFß signaling plays critical roles in the progression of multiple cancers; however, the functional mechanism of this signaling network in the infectious milieu of Esophageal Squamous Cell Carcinoma (ESCC) remains largely unknown. In this study, by using global transcriptomic analysis, we found that Porphyromonas gingivalis infection increased TGFß secretion and promoted the activation of TGFß/Smad signaling in cultured cells and in clinical ESCC samples. Furthermore, we demonstrated for the first time that P. gingivalis enhanced the expression of Glycoprotein A repetitions predominant (GARP), thereby activating TGFß/Smad signaling. Moreover, the increased GARP expression and the subsequent TGFß activation was partially dependent on the fimbriae (FimA) of P. gingivalis. Intriguingly, eliminating P. gingivalis, inhibiting TGFß, or silencing GARP led to a decreased phosphorylation of Smad2/3, the central mediator of TGFß signaling, as well as an attenuated malignant phenotype of ESCC cells, indicating that the activation of TGFß signaling could be an adverse prognostic factor of ESCC. Consistently, our clinical data demonstrated that the phosphorylation of Smad2/3 and the expression of GARP were positively correlated to the poor prognosis of ESCC patients. Lastly, using xenograft models, we found that P. gingivalis infection remarkably activated TGFß signaling and subsequently enhanced the tumor growth and lung metastasis. Collectively, our study indicated that TGFß/Smad signaling mediates the oncogenic function of P. gingivalis in ESCC, which is augmented by the expression of GARP. Therefore, targeting either P. gingivalis or GARP-TGFß signaling could be a potential treatment strategy for patients with ESCC.

Frequencies of Porphyromonas gingivalis Detection in Oral-Digestive Tract Tumors.

Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. In this study, we examined the presence of Porphyromonas gingivalis (P. gingivalis) in oral-digestive tract tumors by immunohistochemistry (IHC) and PCR and analyzed the correlation between P. gingivalis detection and clinicopathological characteristics and prognosis of oral and esophageal carcinoma. The IHC results showed that the positive rates of P. gingivalis were 60.00, 46.00, 20.00, 6.67, and 2.86% in oral, esophagus, cardiac, stomach, and colorectal cancer tissues, respectively. Likewise, PCR results showed rates of 56.00, 42.00, 16.67, 3.33, and 2.86%, respectively. The two methods were consistent, and the kappa value was 0.806, P < 0.001. In addition, P. gingivalis expression was significantly correlated with lymph node metastasis and the clinical stages of oral and esophageal cancer (P < 0.05). The overall survival rate of the P. gingivalis undetected group (86, 50%) was significantly higher than that of the P. gingivalis detected group (57, 14%) for oral and esophageal cancer, respectively. In conclusion, the detection rate of P. gingivalis showed a decreasing trend in oral-digestive tract tumors. Detection with P. gingivalis was associated with poor prognosis for oral and esophageal cancer.

Different frequencies of Porphyromonas gingivalis infection in cancers of the upper digestive tract.

The high incidence rate of multiple carcinomas in the upper digestive tract is often explained in terms of involvement of the same underlying risk factors. It has been reported that the oral bacterium Streptococcus anginosus is associated with esophageal, gastric, and pharyngeal cancers. We previously reported occurrence of Porphyromonas gingivalis (P. gingivalis) DNA in esophagus cancer. In this study, the presence of P. gingivalis in specimens of various types of cancer from the upper digestive tract was investigated. Here we report that P. gingivalis was preferentially and frequently present in specimens of esophageal cancer as well as in those from dysplasia of the esophagus but rarely in matched noncancerous portions and are quite low or absent in cancers from the cardia or stomach. Therefore, it led us to propose that, the microorganism does not survive in conditions of high acidity. We then investigate the pH dependence of survival of P. gingivalis as well as the acid tolerance of it. We found that, exposure to acidic buffers of a wide range of pH values led to a decline in colony forming units of P. gingivalis, thus, providing a possible explanation for variations in frequencies of P. gingivalis infection in this study.