Expression of TMEM16A in Colorectal Cancer and Its Correlation With Clinical and Pathological Parameters

Abstract

TMEM16A is a recently identified calcium-activated chloride channel (CaCC) and its overexpression contributes to tumorigenesis and progression in several human malignancies. However, little is known about expression of TMEM16A and its clinical significance in colorectal cancer (CRC). TMEM16A mRNA expression was determined by quantitative real time-PCR (qRT-PCR) in 67 CRC tissues and 24 para-carcinoma tissues. TMEM16A protein expression was performed by immunohistochemistry in 80 CRC tissues. The correlation between TMEM16A expression and clinicopathological parameters, and known genes and proteins involved in CRC was analyzed. The results showed that TMEM16A mRNA expression was frequently detected in 51 CRC tissues (76%), whereas TMEM16A protein expression was determined at a relatively lower frequency (26%). TMEM16A mRNA expression in tumor tissues was higher than its expression in normal para-carcinoma tissues (P < 0.05). TMEM16A mRNA expression was significantly correlated with TNM stage (p = 0.039) and status of lymph node metastasis (p = 0.047). In addition, there was a strong positive correlation between TMEM16A mRNA expression and MSH2 protein. More importantly, TMEM16A protein expression was positively associated with KRAS mutation, and negatively correlated with mutant p53 protein. Logistic regression analysis demonstrated that TMEM16A mRNA expression was an important independent predictive factor of lymph node metastasis (OR = 16.38, CI: 1.91–140.27, p = 0.01). TMEM16A mRNA and protein expression was not significantly related with patient survival. Our findings provide original evidence demonstrating TMEM16A mRNA expression can be a novel predictive marker of lymph node metastasis and TMEM16A protein expression may be an important regulator of tumor proliferation and metastasis in CRC.

Long-term survival of an adult patient with undifferentiated embryonal sarcoma of the liver with multidisciplinary treatment: a case report and literature review

“…DOG-1 is a member of the transmembrane protein 16 family, featured as a calcium-activated chloride channel and expressed in GIST, but the detailed functions are unknown. Recently, the details of DOG-1 have been revealed gradually by reported expression in poorly differentiated tumors [21,22], such as sarcomatous carcinoma of the liver, in lymph node metastasis of colorectal cancer [23], and as a poor prognostic factor in breast cancer [24]. The clinical significance of DOG-1 positivity in UESL is unclear; however, it may become more evident with the accumulation of cases.…”

Impact of KRAS mutation on the tumor microenvironment in colorectal cancer

“…KRAS mutation, which is more common in right-sided colon cancer (RCC) than in left-sided colon cancer (LCC), is correlated with a negative prognosis in LCC patients but not in RCC patients 5 . In addition, KRAS mutation is positively correlated with the TMEM16A protein, a calcium-activated chloride channel associated with tumorigenesis and progression in various cancers 6 . However, patients harboring multiple KRAS mutations have better prognoses than those harboring a single mutation 7 .…”

TMEM16A as a potential treatment target for head and neck cancer

“…Therefore, TMEM16A can serve as a biomarker for clinical outcomes and breast cancer therapeutic responses to tamoxifen [ 5 ]. In colorectal cancer (CRC), Li et al reported that TMEM16A mRNA expression could be a novel predictive marker of LNM, and TMEM16A expression may be an important regulator of tumor proliferation and metastasis [ 34 ]. Moreover, Liu et al (2015) found that high expression levels of TMEM16A were associated with LNM, higher disease grade, and poor prognosis of gastric cancer (GC) [ 35 ], whereas Liu et al (2012) confirmed a positive correlation between TMEM16A expression and tumor grade in prostate cancer [ 36 ].…”

“…TMEM16A overexpression correlates with improved clinical outcomes following chemotherapy [ 34 ]. Vyas et al reported a strong positive correlation between TMEM16A and ATP7B expressions, which balances the copper level in the body by excreting excess copper into bile and plasma in HNSCC.…”

“…A previous study showed that increased oxidative stress in cells overexpressing TMEM16A liberated the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression, which in turn decreased the efficacy of platinum compounds by promoting their vesicular sequestration [ 63 ]. TMEM16A also promotes the sensitivity of other antitumor agents [ 47 , 64 ], and TMEM16A overexpression could correlate with the deterioration of clinical outcomes by chemotherapy [ 34 ]. Platinum-based chemotherapy is the cornerstone treatment for a variety of human malignancies, including HNSCC.…”