New breakthrough in early cancer screening: "Molecular fishing hook" captures "invisible signals"

Produced by: Science Popularization China

Author: Wang Tingting, Miao Peng (Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences)

Producer: China Science Expo

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In recent years, due to factors such as diet, environment, and population aging, the global incidence of cancer has continued to rise, and cancer has gradually become the biggest killer of people's lives. Recently, the National Cancer Center released the 2024 National Cancer Report, which provides the latest statistics on new cancer cases and mortality rates in China in 2022.

Survey data show that in 2022, the number of new cancer cases in China will be about 4.8247 million, and the number of new cancer cases will be about 2.5742 million. The top five new cancers are: lung cancer, colorectal cancer, thyroid cancer, liver cancer, and gastric cancer.

Anti-cancer

(Image source: pixabay)

The key to preventing cancer is early diagnosis and early treatment

Reading this data makes people shudder! What's more frightening is that some of the early signs of cancer are nasal congestion, bloody nasal discharge, nosebleeds, tinnitus, earache, unexplained persistent low-grade fever, abnormal lumps, ulcers that do not heal, and other prominent symptoms.

However, most cancers usually have no obvious symptoms in the early stages, and the progression of cancer is often very rapid. If you wait until symptoms appear before seeking medical help, the cancer may have already progressed to the late stage, when treatment becomes much more difficult and complex.

If we can diagnose cancer in its early stages, we can completely cure it through surgery and other methods. Therefore, the most critical measure to prevent cancer is "early diagnosis and early treatment."

Common methods for early cancer screening include X-rays, ultrasound, gastroscopy, colonoscopy, etc. However, these methods not only make the subjects suffer, but also have disadvantages such as low sensitivity, long time and high price.

So, is there any good way to efficiently and sensitively detect whether people have cancer?

miRNA can be used as an "invisible signal" for early cancer screening

Here we have to introduce "miRNA", also known as microRNA, which is a very small nucleic acid. The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros and Gary Ruvkun for their discovery of miRNA and its role in post-transcriptional gene regulation.

Many of you may wonder what miRNA is, what it does, and why it is given such a high honor?

We all know that humans are advanced animals with language, thinking, and cognition, but the number of genes in humans is similar to that in ducks, flies, and even bananas ! Many friends may be shocked. What causes such a big difference? Most of these are due to miRNA.

Each gene in an organism is like a flashlight in a room, which can be turned on and off, and the intensity of the light can be adjusted. Although the number of flashlights is the same, different lighting conditions and different light brightness will eventually lead to different brightness in the room. The difference between species is similar to this principle. miRNA plays the role of gene switch, controlling the expression of specific genes. Every cell in our body has its own job, and microRNA is no exception.

miRNA exists in every cell and can stably circulate in the blood. They are the source of health signals in the body. If our body is damaged by bacterial infection, viral invasion, etc., the level of miRNA will change significantly to inform us of the danger. Especially in the prevention of cancer, as long as we receive abnormal signals from miRNA, we can predict the risk one step ahead of the disease.

Designing a 'molecular hook' to capture cancer's 'invisible signals'

So, how can we accurately know the relationship between the signals emitted by miRNA and specific diseases?

We need to develop a flexible, efficient and accurate detection system.

Our team (Miao Peng's group at the Suzhou Institute of Biomedical Engineering, Chinese Academy of Sciences) has been committed to the detection of cancer-related miRNA for many years. Through detailed research on the structure of nucleic acids, we have cleverly designed a "molecular hook", namely the "DNA truncated cone nanostructure", which can sensitively and quickly capture the "invisible signal" prey molecule miRNA of cancer.

Here we need to introduce the concept of "nano". If a hair is cut along its diameter and then divided into 100,000 parts, the diameter of each new hair is 1 nanometer. Therefore, the DNA nanostructure is very small and can flow freely in many scenarios in the body.

So, how are nanoscale DNA truncated cone structures assembled?

Most of us have played the Lego building game, where different geometric models are built by assembling blocks of different shapes in different ways. The assembly of DNA truncated cones is similar to this principle. We need to design different DNA molecules to replace various building blocks and form the spatial structure of the truncated cone according to certain rules.

The process of "molecular hook" capturing "invisible signal"

(Image source: Reference 2)

We first assembled a DNA triangle with four chains (TPF1, TPF2, TPF3, TPF4) and fixed it on the surface of a gold electrode. TPF1, TPF2, and TPF3 all carry a group tag called DBCO. We also have a special chain (TPF5) that serves as a "bait" chain to capture "prey" miRNA. Its specific region can bind to the three chains TPF1, TPF2, and TPF3, thereby sealing the DBCO group in the "molecular hook" truncated cone.

Because TPF5 has a stronger binding affinity to miRNA, miRNA will preferentially bind to TPF5. Therefore, when the "prey" miRNA appears, TPF5 acts like a "bait."

When the bait TPF5 binds to the prey miRNA, the top of the originally closed truncated cone will open and return to an open triangular structure. At this time, there will be a double-stranded specific nuclease called DSN, which is like a pair of scissors that can cut the bound TPF5 and miRNA hybrid chain, allowing the miRNA to "regain freedom". In this way, the released "prey" miRNA can once again bind to the "bait" TPF5 on another truncated cone, thereby capturing more TPF5.

After many cycles, almost all the truncated cones become open triangular structures. At this time, the "prey" miRNA has also captured enough "bait". When the "bait" TPF5 is lost too much, the chains with DBCO tags (TPF1, TPF2, TPF3) will be exposed. At this time, they will bind to another probe chain P1 with an N3 group at one end, thereby forming a special hairpin structure on the surface of the gold electrode.

Since the other end of the probe P1 chain carries the signal molecule ferrocene, we can observe significant changes in the current peak through the electrochemical working platform. When the concentration of miRNA increases, the peak of the current curve will become higher and higher.

On the contrary, when miRNA does not appear, the DBCO group is enclosed in the truncated cone, the TPF chain cannot bind to the P1 chain, the hairpin structure cannot be formed on the electrode surface, and no obvious peak can be observed in the voltammetric curve. In this way, we can indirectly determine the content of the "invisible signal" miRNA by measuring the peak of the curve, thereby realizing the prediction of diseases in advance.

This strategy of using "molecular hooks" to capture cancer "invisible signals" is advanced in conception and ingenious in design, and can help detect a variety of high-risk precancerous lesions at an early stage.

In the future, "molecular hooks" are expected to be used in clinical cancer early screening

The truncated cone, which serves as a "molecular hook", is assembled from nucleic acid chains in the human body and has a high degree of biocompatibility, which is expected to be used in clinical practice. During the test, only a small amount of serum from the person being tested is needed, and the result can be obtained after waiting for 30 minutes for the reaction. If the value of miRNA exceeds the standard range, it indicates that the person being tested may be at risk of cancer, and should go to the hospital for further examination in time to achieve the purpose of early detection, early treatment and early recovery of health.

Life is unknown, but we can use the power of science and technology to "discover" risks as early as possible, so as to intervene as early as possible. Instead of being afraid of cancer, it is better to prevent it before it happens. Let's act together and cheer for health!

References:

(1)Han, BF; Zheng, RS; Zeng, HM; Wang, SM; Sun, KX; Chen, R.; Li, L.; Wei, WQ; He, J. Cancer Incidence and Mortality in China, 2022. Journal of the National Cancer Center 2024, 4, 47-53.

(2)Wang, TT; Zheng, XY; Chai, H.; Miao, P. DNA Nanostructure Disintegration-Assisted SPAAC Ligation for Electrochemical Biosensing. Nano Letters 2024, 24, 12233-12238.

(3)Lee, RC; Feinbaum, RL; Ambros, V. The C. Elegans Heterochronic Gene Lin-4 Encodes Small RNAs with Antisense Complementarity to Lin-14. Cell 1993, 75, 843-854.